Purpose: This study aimed to explore the effects of a 10-week combined exercise regimen on immobilizationinduced muscle atrophy and elucidate the possible function of Protein arginine methyltransferase 1(Prmt1) in thi...Purpose: This study aimed to explore the effects of a 10-week combined exercise regimen on immobilizationinduced muscle atrophy and elucidate the possible function of Protein arginine methyltransferase 1(Prmt1) in this process.Methods: 8-week-old male C57BL/6J mice were carried out combined exercise for 10 weeks. One week before the end of the intervention, mice underwent cast immobilization. Additionally, to investigate the potential mechanism in exercise-induced protection of skeletal muscle, mice in the exercise preconditioning group were administered TC-E-5003(an inhibitor of Prmt1 enzymatic activity). Exercise performance, muscle mass, and the cross-sectional area(CSA) of muscle fibers were analyzed. Besides, Prmt1 and Sestrin1(Sesn1) were either overexpressed or inhibited in C2C12 myotubes to elucidate the underlying mechanism.Results: Exercise preconditioning not only significantly improved muscle mass and motor ability in immobilized mice but also inhibited excessive activation of degradation pathways and enhanced protein synthesis. Importantly, Prmt1 mediated the protective effects of exercise preconditioning on muscle atrophy. Mechanistically,Prmt1 regulated the p38 mitogen-activated protein kinase(p38)/activating transcription factor 2(ATF2)pathway, which modulates Sesn1 expression. Sesn1 acts as a downstream of Prmt1 and ATF2, contributing to the myoblast differentiation and skeletal muscle regeneration through AMP-Activated protein kinase α2(AMPKα2)/transcriptional co-activator PPAR-γ co-activator-1 α(PGC-1α) signaling pathway.Conclusions: Taken together, our results highlighted the effectiveness of exercise preconditioning in preventing muscle atrophy via the Prmt1-Sesn1 pathway.展开更多
Resistance exercise has been confirmed to be important for maintaining muscle mass and function.However,despite considerable experimental studies,the underlying mechanisms still requires further investigation to be el...Resistance exercise has been confirmed to be important for maintaining muscle mass and function.However,despite considerable experimental studies,the underlying mechanisms still requires further investigation to be elucidated.Sestrin1 is a stress-inducible protein strongly associated with the occurrence and development of skeletal muscle dysfunction.Besides,oxidative stress is believed to be a major pathogenic mechanism in the development of skeletal muscle atrophy,whereas regular exercise training induces the endogenous antioxidative system and protects the body against adverse effects of oxidative stress.Nevertheless,whether Sestrin1 is involved in the amelioration of resistance exercise on muscle atrophy and the role of its antioxidant function in this process remains unknown.Here we show that six-week resistance exercise training significantly improved muscle function,muscle mass,and oxidative damage and maintained the level of Sestrin1 in dexamethasone-treated C57BL/6J mice.Mechanistically,Sestrin1 overexpression rescued protein degradation and oxidative stress in atrophied myotubes.Furthermore,an emerging regulator of cellular defense against toxic and oxidative insults,nuclear factor erythroid2–related factor 2(Nrf2)controls the basal and induced expression of an array of antioxidant response element–dependent genes to regulate the pathophysiological outcomes of oxidant exposure.In this study,we found that Nrf2 is a target of Sestrin1,and Nrf2 nuclear translocation is facilitated by Sestrin1.ML385(an Nrf2 inhibitor)treatment mitigated the regulatory effects of overexpression-Sestrin1.Therefore,Sestrin1 was involved in the process of resistance exercise against skeletal muscle atrophy,which may be closely related to its antioxidant capacity,revealing a potential therapeutic strategy for reducing the loss of skeletal muscle.展开更多
Muscle atrophy can be induced by high doses or prolonged use of glucocorticoids.Kaempferol(Kae)is a naturally occurring flavonoid with a variety of biological activities and the effect of Kae on dexamethasone(Dex)indu...Muscle atrophy can be induced by high doses or prolonged use of glucocorticoids.Kaempferol(Kae)is a naturally occurring flavonoid with a variety of biological activities and the effect of Kae on dexamethasone(Dex)induced muscle atrophy in animals has not been elucidated.To explore this issue,the present experiments used a computationally assisted drug design scheme combining network pharmacology,molecular docking and in vivo experiments to investigate the mechanism of Kae against muscle atrophy.Network pharmacological analyses revealed 275 potential targets for Kae and 12294 potential targets for muscle atrophy,with a total of 228 crosstargets for Kae and muscle atrophy.GO and KEGG analyses were performed based on the protein-protein interaction(PPI)network of muscle atrophy and Kae component targets.The GO results showed that the biological processes were mainly related to the metabolic process of reactive oxygen species,and the response to oxidative stress;the cellular components were mainly focused on membrane microdomains,and membrane regions;the molecular functions mainly worked on phosphatase binding;and the KEGG pathway enrichment analyses identified the pathways of interaction between Kae and muscle atrophy.Finally,as verified by in vivo experiments,Kae may reduce the onset of muscle atrophy by activating the PI3K/AKT/m TOR/signalling pathway,inhibiting Foxo1/Foxo3 activity,and inhibiting downstream production of the ubiquitination 3 ligases Atrogin1 and Mu RF1;Kae also promotes the expression of NRF2/HO-1/KEAP1 signalling pathway,enhances muscle antioxidant capacity,inhibits the release of COX-2 and TNF-αinflammatory factors,and reduces the damage caused by oxidative stress and inflammatory factors to muscles.Therefore,there may be a synergistic effect of PI3K/AKT/m TOR and NRF2/HO-1/KEAP1 in Kae working together to prevent muscle atrophy.The binding energy and stability of Kae to potential targets were examined by molecular docking and molecular dynamics simulations,implying that Kae could be used for the prevention and treatment of muscle atrophy in patients.展开更多
Objective:To evaluate the efficacy and safety of transcutaneous electrical acupoint stimulation(TEAS)for muscle atrophy in patients with immobilization after surgical fixation of foot and ankle fractures.Methods:This ...Objective:To evaluate the efficacy and safety of transcutaneous electrical acupoint stimulation(TEAS)for muscle atrophy in patients with immobilization after surgical fixation of foot and ankle fractures.Methods:This was a two-arm randomized controlled trial wherein 80 patients were recruited and divided into control(n=40)and intervention(n=40)groups.The control group received conventional orthopedic treatment,whereas the intervention group received TEAS and conventional treatment.The intervention group received TEAS 3 times a week for 30 min each time for 8 weeks.The primary out-comes were muscle thickness(MT)and cross-sectional area(CSA)of the rectus femoris and gastroc-nemius muscles,whereas the secondary outcome measure was echo intensity(EI).Data were collected before the fixation operations(baseline assessment)and 4 and 8 weeks after intervention.Results:Compared with baseline,the MT and CSA were reduced in both groups by the end of treatment,whereas EI increased in both groups.At week 4,the reduction in the rectus femoris CSA in the inter-vention group was significantly lower than that in the control group(P=0.02);however,the between-group differences in the MT and EI(all P>0.05)were not significant.No serious adverse events were observed in either group.Conclusion:Our study showed that TEAS can improve muscle atrophy by attenuating the decline in the muscle CSA.Because this was only a pilot trial,subsequent studies will need longer follow-ups and larger sample sizes.展开更多
Skeletal muscle atrophy results from disruptions in the growth and metabolism of striated muscle,leading to a reduction or loss of muscle fibers.This condition not only significantly impacts patients’quality of life ...Skeletal muscle atrophy results from disruptions in the growth and metabolism of striated muscle,leading to a reduction or loss of muscle fibers.This condition not only significantly impacts patients’quality of life but also imposes substantial socioeconomic burdens.The complex molecular mechanisms driving skeletal muscle atrophy contribute to the absence of effective treatment options.Recent advances in stem cell therapy have positioned it as a promising approach for addressing this condition.This article reviews the molecular mechanisms of muscle atrophy and outlines current therapeutic strategies,focusing on mesenchymal stem cells,induced pluripotent stem cells,and their derivatives.Additionally,the challenges these stem cells face in clinical applications are discussed.A deeper understanding of the regenerative potential of various stem cells could pave the way for breakthroughs in the prevention and treatment of muscle atrophy.展开更多
Obesity is associated with skeletal muscle mass loss and physical dysfunction.Krill oil(KO)has been shown to be beneficial in human health.However,the effect of KO on obesity-induced skeletal muscle atrophy is still u...Obesity is associated with skeletal muscle mass loss and physical dysfunction.Krill oil(KO)has been shown to be beneficial in human health.However,the effect of KO on obesity-induced skeletal muscle atrophy is still unclear.In this study,the male C57BL/6J mice were fed a high-fat diet(HFD)for 12 weeks to induce obesity,and then were intragastric administration with 400 mg/kg bw KO for an additional 6 weeks.The results showed that KO treatment reduced body weight,fat accumulation and serum pro-inflammatory cytokines in HFD-induced obese mice.Importantly,KO treatment attenuated skeletal muscle atrophy in HFD-fed mice,as evidenced by preserving skeletal muscle mass,average myofiber cross-sectional area and grip strength.KO administration also mitigated obesity-induced ectopic lipid deposition and inflammatory response in skeletal muscle.Additionally,KO treatment inhibited the transcriptional activities of nuclear factor-κB(NF-κB)p65 and forkhead box O 3a(FoxO3a),and then down-regulated muscle atrophy F-box(MAFbx)and muscle-specific RING finger protein 1(MuRF1)protein levels in skeletal muscle from HFD-fed mice.KO administration also improved obesity-induced impaired muscle protein synthesis via activating PI3K/Akt pathway.Furthermore,KO treatment enhanced muscle mitochondrial biogenesis in HFD-induced obese mice via activating PGC-1αpathway.Collectively,KO might be developed as a potential nutritional supplement for the prevention and treatment of obesity-induced skeletal muscle atrophy.展开更多
Background:The aim of this study was to analyze the bi-directional causal relation-ship between lipid profile and characteristics related to muscle atrophy by using a bi-directional Mendelian randomization(MR)analysis...Background:The aim of this study was to analyze the bi-directional causal relation-ship between lipid profile and characteristics related to muscle atrophy by using a bi-directional Mendelian randomization(MR)analysis.Methods:The appendicular lean mass(ALM),whole body fat-free mass(WBFFM)and trunk fat-free mass(TFFM)were used as genome-wide association study(GWAS)data for evaluating muscle mass;the usual walking pace(UWP)and low grip strength(LGS)were used as GWAS data for evaluating muscle strength;and the triglycerides(TG),total cholesterol(TC),high density lipoprotein cholesterol(HDL),low density lipo-protein cholesterol(LDL),apolipoprotein A-1(Apo A-1),and apolipoprotein B(Apo B)were used as GWAS data for evaluating lipid profile.For specific investigations,we mainly employed inverse variance weighting for causal estimation and MR-Egger for pleiotropy analysis.Results:MR results showed that the lipid profile predicted by genetic variants was negatively correlated with muscle mass,positively correlated with UWP,and was not causally correlated with LGS.On the other hand,the muscle mass predicted by genetic variants was negatively correlated with lipid profile,the UWP predicted by genetic variants was mainly positively correlated with lipid profile,while the LGS pre-dicted by genetic variants had no relevant causal relationship with lipid profile.Conclusions:Findings of this MR analysis suggest that hyperlipidemia may affect muscle mass and lead to muscle atrophy,but has no significant effect on muscle strength.On the other hand,increased muscle mass may reduce the incidence of dyslipidemia.展开更多
Delay of axon regeneration after peripheral nerve injury usually leads to progressive muscle atrophy and poor functional recovery. The Wnt/β-catenin signaling pathway is considered to be one of the main molecular mec...Delay of axon regeneration after peripheral nerve injury usually leads to progressive muscle atrophy and poor functional recovery. The Wnt/β-catenin signaling pathway is considered to be one of the main molecular mechanisms that lead to skeletal muscle atrophy in the elderly. We hold the hypothesis that the innervation of target muscle can be promoted by accelerating axon regeneration and decelerating muscle cell degeneration so as to improve functional recovery of skeletal muscle following peripheral nerve injury. This process may be associated with the Wnt/β-catenin signaling pathway. Our study designed in vitro cell models to simulate myelin regeneration and muscle atrophy. We investigated the effects of SB216763, a glycogen synthase kinase 3 beta inhibitor, on the two major murine cell lines RSC96 and C2C12 derived from Schwann cells and muscle satellite cells. The results showed that SB216763 stimulated the Schwann cell migra- tion and myotube contraction. Quantitative polymerase chain reaction results demonstrated that myelin related genes, myelin associated glycoprotein and cyclin-D1, muscle related gene myogenin and endplate-associated gene nicotinic acetylcholine receptors levels were stimulated by SB216763. Immunocytochemical staining revealed that the expressions of ^-catenin in the RSC96 and C2C12 cytosolic and nuclear compartments were increased in the SB216763-treated cells. These findings confirm that the glycogen synthase kinase 3 beta in- hibitor, SB216763, promoted the myelination and myotube differentiation through the Wnt/β-catenin signaling pathway and contributed to nerve remyelination and reduced denervated muscle atrophy after peripheral nerve injury.展开更多
Background:Exercise is beneficial for muscle atrophy.Peroxisome proliferator-activated receptor gamma(PPARγ) and microRNA-29 b(miR-29 b) have been reported to be responsible for angiotensinⅡ(AngⅡ)-induced muscle at...Background:Exercise is beneficial for muscle atrophy.Peroxisome proliferator-activated receptor gamma(PPARγ) and microRNA-29 b(miR-29 b) have been reported to be responsible for angiotensinⅡ(AngⅡ)-induced muscle atrophy.However,it is unclear whether exercise can protect AngⅡ-induced muscle atrophy by targeting PPARγ/miR-29 b.Methods:Skeletal muscle atrophy in both the control group and the run group was established by AngⅡ infusion;after 1 week of exercise training,the mice were sacrificed,and muscle weight was determined.Myofiber size was measured by hematoxylin-eosin and wheat-germ agglutinin staining.Apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling staining.The expression level of muscle atrogenes,including F-box only protein 32(FBXO32,also called Atrogin-1) and muscle-specific RING-finger 1(MuRF-1),the phosphorylation level of protein kinase B(PKB,also called AKT)/forkhead box 03 A(FOX03 A)/mammalian target of rapamycin(mTOR) pathway proteins,the expression level of PPARγ and apoptosis-related proteins,including B-cell lymphoma-2(Bcl-2),Bcl-2-associated X(Bax),cysteine-aspartic acid protease 3(caspase-3),and cleaved-caspase-3,were determined by western blot.The expression level of miR-29 b was checked by reversetranscription quantitative polymerase chain reaction.A PPARγ inhibitor(T0070907) or adeno-associated virus serotype-8(AAV8)-mediated miR-29 b overexpression was used to demonstrate whether PPARγ activation or miR-29 b inhibition mediates the beneficial effects of exercise in AngⅡ-induced muscle atrophy.Results:Exercise can significantly attenuate AngⅡ-induced muscle atrophy,which is demonstrated by increased skeletal muscle weight,cross-sectional area of myofiber,and activation of AKT/mTOR signaling and by decreased atrogenes expressions and apoptosis.In AngⅡ-induced muscle atrophy mice models,PPARγ was elevated whereas miR-29 b was decreased by exercise.The protective effects of exercise in AngⅡ-induced muscle atrophy were inhibited by a PPARγ inhibitor(T0070907) or adeno-associated virus serotype-8(AAV8)-mediated miR-29 b overexpression.Conclusion:Exercise attenuates AngⅡ-induced muscle atrophy by activation of PPARγ and suppression of miR-29 b.展开更多
We examined the effect of a combination of astaxanthin （AX） supplementation, repeated heat stress, and intermittent reloading （IR） on satellite cells in unloaded rat soleus muscles. Forty-nine male Wistar rats （8...We examined the effect of a combination of astaxanthin （AX） supplementation, repeated heat stress, and intermittent reloading （IR） on satellite cells in unloaded rat soleus muscles. Forty-nine male Wistar rats （8-week-old） were divided into control, hind-limb unweighting （HU）, IR during HU, IR with AX supplementation, IR with repeated heat stress （41.0-41.5 ℃ for 30 min）, and IR with AX supplementation and repeated heat stress groups. After the experimental period, the antigravitational soleus muscle was analyzed using an immunohistochemical technique. Our results revealed that the combination of dietary AX supplementation and heat stress resulted in protection against disuse muscle atrophy in the soteus muscle. This protective effect may be partially due to a higher satellite cell number in the atrophied soleus muscle in the IR/AX/heat stress group compared with the numbers found in the other groups. We concluded that the combination treatment with dietary AX supplementation and repeated heat stress attenuates soleus muscle atrophy, in part by increasing the number of satellite cells.展开更多
We recently demonstrated a repurposing beneficial effect of 4-aminopyridine(4-AP),a potassium channel blocker,on functional recove ry and muscle atrophy after sciatic nerve crush injury in rodents.However,this effect ...We recently demonstrated a repurposing beneficial effect of 4-aminopyridine(4-AP),a potassium channel blocker,on functional recove ry and muscle atrophy after sciatic nerve crush injury in rodents.However,this effect of 4-AP is unknown in nerve transection,gap,and grafting models.To evaluate and compare the functional recovery,nerve morphology,and muscle atrophy,we used a novel stepwise nerve transection with gluing(STG),as well as 7-mm irreparable nerve gap(G-7/0)and 7-mm isografting in 5-mm gap(G-5/7)models in the absence and presence of 4-AP treatment.Following surgery,sciatic functional index was determined wee kly to evaluate the direct in vivo global motor functional recovery.After 12 weeks,nerves were processed for whole-mount immunofluorescence imaging,and tibialis anterior muscles were harvested for wet weight and quantitative histomorphological analyses for muscle fiber crosssectional area and minimal Feret's diameter.Average post-injury sciatic functional index values in STG and G-5/7 models were significantly greater than those in the G-7/0 model.4-AP did not affect the sciatic functional index recovery in any model.Compared to STG,nerve imaging revealed more misdirected axons and distorted nerve architecture with isografting.While muscle weight,cross-sectional area,and minimal Feret's diameter were significantly smaller in G-7/0 model compared with STG and G-5/7,4-AP treatment significantly increased right TA muscle mass,cross-sectional area,and minimal Feret's diameter in G-7/0 model.These findings demonstrate that functional recovery and muscle atrophy after peripheral nerve injury are directly related to the intervening nerve gap,and 4-AP exerts diffe rential effects on functional recove ry and muscle atrophy.展开更多
Objective To compare the cross section area (CSA) and the immunoreactivity of conjugated ubiquitin in soleus extrafusal and intrafusal fibers after simulated microgravity and to demonstrate the role of muscle spin...Objective To compare the cross section area (CSA) and the immunoreactivity of conjugated ubiquitin in soleus extrafusal and intrafusal fibers after simulated microgravity and to demonstrate the role of muscle spindle in muscle atrophy induced by simulated microgravity. Methods The immunohistochemical technique (ABC) and image analysis were used to assess the conjugated ubiquitin immunostaining and the cross sectional area of intrafusal and extrafusal fibers of soleus in simulated microgravity rats. Results ①Tail suspension caused a progressive loss of soleus mass. Mean fiber CSA of extrafusal fibers were (7±2)%, (21±4)% and (32±7)% smaller after 3 days, 7 days and 14 days suspension, respectively. While the CAS of intrafusal fibers (bag + chain fibers) were (14±3)% ( P < 0.05 ), (30±7)% ( P < 0.01 ) and (44±10)% ( P < 0.01 ) smaller after 3 days, 7 days and 14 days suspension. ② The immunoreactivity of conjugated ubiquitin both in extrafusal and intrafusal fibers increased after tail suspension. The immunoreactivity of intrafusal fibers increased 1 day after suspension and reached the hightest level at 3 days after tail suspension. The immunoreactivity of extrafusal fibers increased after 3 days suspension and reached the highest level after 7 days tail suspension, which was lower than that in intrafusal fibers after 3 days tail suspension. Conclusion These results suggest that soleus atrophy of intrafusal fibers caused by tail suspension is earlier and more severe than that in extrafusal fibers.展开更多
Denervation-induced skeletal muscle atrophy can potentially cause the decline in the quality of life of patients and an increased risk of mortality.Complex pathophysiological mechanisms with dynamic alterations have b...Denervation-induced skeletal muscle atrophy can potentially cause the decline in the quality of life of patients and an increased risk of mortality.Complex pathophysiological mechanisms with dynamic alterations have been documented in skeletal muscle atrophy resulting from innervation loss.Hence,an in-depth comprehension of the key mechanisms and molecules governing skeletal muscle atrophy at varying stages,along with targeted treatment and protection,becomes essential for effective atrophy management.Our preliminary research categorizes the skeletal muscle atrophy process into four stages using microarray analysis.This review extensively discusses the pathways and molecules potentially implicated in regulating the four stages of denervation and muscle atrophy.Notably,drugs targeting the reactivare oxygen species stage and the inflammation stage assume critical roles.Timely intervention during the initial atrophy stages can expedite protection against skeletal muscle atrophy.Additionally,pharmaceutical intervention in the ubiquitin-proteasome pathway associated with atrophy and autophagy lysosomes can effectively slow down skeletal muscle atrophy.Key molecules within this stage encompass MuRF1,MAFbx,LC3II,p62/SQSTM1,etc.This review also compiles a profile of drugs with protective effects against skeletal muscle atrophy at distinct postdenervation stages,thereby augmenting the evidence base for denervation-induced skeletal muscle atrophy treatment.展开更多
Objective:To find the key targets of muscle atrophy after spinal cord injury(SCI)were excavated,to construct the lncRNA-miRNA-mRNA regulatory network based on bioinformatics analysis,and to verify the expression chang...Objective:To find the key targets of muscle atrophy after spinal cord injury(SCI)were excavated,to construct the lncRNA-miRNA-mRNA regulatory network based on bioinformatics analysis,and to verify the expression changes of key regulatory networks in muscle atrophy after SCI by animal experiments,so as to seek new research directions for the pathogenesis and treatment of muscle atrophy after SCI.Methods:The GSE21497 data set was downloaded from the GEO database for differential expression gene screening and WGCNA treatment.Combined with the online prediction database,key mRNAs were screened out.GO and KEGG enrichment analyses of key mRNAs were performed using the DAVID database to construct the lncRNA-miRNA-mRNA regulatory network.The key regulatory genes were selected and then verified by RT-qPCR.Results:A total of 1405 differentially expressed genes were screened,and 30 key mRNAs were predicted by the WGCNA and online database.GO and KEGG enrichment analyses showed that it was mainly enriched in the functions of neuron regeneration,protection,signal transmission,the HIF signaling pathway,PD-L1 expression and the PD-1 checkpoint pathway.Four key regulatory networks were identified(LINC00410/miR-17-5p/KCNK10,LINC00410/miR-17-5p/PCDHA3,LINC00410/miR-20b-5p/KCNK10,LINC00410/miR-20b-5p/PCDHA3).The results of RT-qPCR showed that,compared with the control group,the expression of miR-17-5p and miR-20b-5p in the observation group increased,and the expression of KCNK10 and PCDHA3 decreased.Conclusions:MiR-17-5p,miR-20b-5p,KCNK10,and PCDHA3 may play an important regulatory role in the regeneration,protection,and signal transmission of neurons,which is expected to become a new target for the diagnosis and treatment of muscle atrophy after SCI.展开更多
Over the course of several decades,robust research has firmly established the significance of mitochondrial pathology as a central contributor to the onset of skeletal muscle atrophy in individuals with diabetes.Howev...Over the course of several decades,robust research has firmly established the significance of mitochondrial pathology as a central contributor to the onset of skeletal muscle atrophy in individuals with diabetes.However,the specific intricacies governing this process remain elusive.Extensive evidence highlights that individuals with diabetes regularly confront the severe consequences of skeletal muscle degradation.Deciphering the sophisticated mechanisms at the core of this pathology requires a thorough and meticulous exploration into the nuanced factors intricately associated with mitochondrial dysfunction.展开更多
As a key coordinator of metabolism,AMP-activated protein kinase(AMPK)is vitally involved in skeletal muscle maintenance.AMPK exerts its cellular effects through its function as a serine/threonine protein kinase by reg...As a key coordinator of metabolism,AMP-activated protein kinase(AMPK)is vitally involved in skeletal muscle maintenance.AMPK exerts its cellular effects through its function as a serine/threonine protein kinase by regulating many downstream targets and plays important roles in the development and growth of skeletal muscle.AMPK is activated by phosphorylation and exerts its function as a kinase in many processes,including synthesis and degradation of proteins,mitochondrial biogenesis,glucose uptake,and fatty acid and cholesterol metabolism.Skeletal muscle atrophy is a result of various diseases or disorders and is characterized by a decrease in muscle mass.The pathogenesis and therapeutic strategies of skeletal muscle atrophy are still under investigation.In this review,we discuss the role of AMPK in skeletal muscle metabolism and atrophy.We also discuss targeting AMPK for skeletal muscle treatment,including exercise,AMPK activators including 5-amino-4-imidazolecarboxamide ribonucleoside and metformin,and low-level lasers.These studies show the important roles of AMPK in regulating muscle metabolism and function;thus,the treatment of skeletal muscle atrophy needs to take into account the roles of AMPK.展开更多
The depressed protein synthetic response,a phenomenon termed anabolic resistance,has been shown to be involved in muscle wasting induced by cancer cachexia.Moreover,a positive relationship between the protein syntheti...The depressed protein synthetic response,a phenomenon termed anabolic resistance,has been shown to be involved in muscle wasting induced by cancer cachexia.Moreover,a positive relationship between the protein synthetic rate and intracellular glutamine(GLN)concentration has been found in skeletal muscles.This study investigated the effects of neuromuscular electrical stimulation(ES)and GLN administration on muscle wasting and GLN metabolism in colon-26(C-26)tumor-bearing mice.CD2F1 mice were divided into 8 groups:control(CNT),CNT+ES,CNT+GLN,CNT+ES+GLN,C-26,C-26+ES,C-26+GLN,C-26+ES+GLN.Cancer cachexia was induced by subcutaneous injection of C-26 cells and developed for four weeks.ES was performed on the left plantar flexor muscles every other day,and GLN(1 g/kg)was administered daily intraperitoneally starting one day after the C-26 injection.Tumor-free body mass and fast-twitch gastrocnemius(Gas)muscle weight were lower in the C-26 group than in the CNT group(-19%and-17%,respectively).Neither ES training nor GLN administration,alone or in combination,ameliorated the loss of Gas muscle weight in the C-26 mice.However,ES training in combination with GLN administration inhibited the increased expression of GLN synthetase(GS)in the C-26 muscles.Thus,it is likely that GLN plays a critical role in muscle protein metabolism and,therefore,can be targeted as a tentative treatment of cancer cachexia.展开更多
Concomitant exotropia is a common chronic eye disease characterized by abnormal movement of the extraocular muscles caused by a functional imbalance of the nerves related to the movement of the extraocular muscles.Thi...Concomitant exotropia is a common chronic eye disease characterized by abnormal movement of the extraocular muscles caused by a functional imbalance of the nerves related to the movement of the extraocular muscles.This study revealed that the expression levels of S-100β and the muscle area decreased in the extraocular muscles of patients with concomitant exotropia,whereas the expression of calcitonin gene-related peptide(CGRP)increased.In CGRP-KO rats,low expression of CGRP was positively correlated with muscle atrophy.Moreover,the expression level of muscle cells,which are fast myosin heavy chain positive and slow myosin positive in CGRP-KO rats,was lower than that in the control group.Drug intervention experiments further confirmed the inhibitory effect of CGRP on muscle atrophy.The level of apoptosis in the extraocular muscles of CGRP-KO rats was significantly greater than that in the control group(P<0.05),and the phosphorylation level of AKT/CREB in the extraocular muscles of patients with concomitant exotropia was greater than that in the control group.The increased expression of CGRP in the extraocular muscles of patients with concomitant exotropia may inhibit the apoptosis of extraocular muscle cells through the AKT/CREB signaling pathway and participate in the protective effect of the extraocular muscles in concomitant exotropia.展开更多
Background and Objective:Cachexia-induced skeletal muscle atrophy is a critical manifestation in Kirsten rat sarcoma viral oncogene homologue(KRAS)-mutant pancreatic cancer(PC)patients,predominantly characterized by a...Background and Objective:Cachexia-induced skeletal muscle atrophy is a critical manifestation in Kirsten rat sarcoma viral oncogene homologue(KRAS)-mutant pancreatic cancer(PC)patients,predominantly characterized by a shift in metabolic equilibrium towards catabolism that accelerates protein degradation in myofibers and leads to muscle atrophy.This metabolic reprogramming not only supports tumor growth but also precipitates energy depletion in skeletal muscle tissues.Exploring these mechanisms reveals potential therapeutic targets in the metabolic and proteolytic pathways associated with KRAS-mutant PC.Methods:A comprehensive search for literature was conducted in PubMed,Web of Science,Google Scholar and other search engines up to May 21st,2024.Studies on PC models and patients were included.Key Content and Findings:The crosstalk between KRAS-mutant PC and skeletal muscle atrophy can be categorized into four principal domains:(I)KRAS-driven metabolic reprogramming in cancer cells leads to the depletion of muscle energy reserves,thereby influencing the reallocation of myofiber energy towards fueling cancer cell;(Ⅱ)KRAS-mutant cancer cells rely on nutrient-scavenging pathways,resulting in altered cytokine profiles,increased ubiquitin mRNA expression and autophagy-lysosome pathway,which facilitate myotube degradation and inhibit muscle regeneration,thereby disrupting muscular homeostasis and causing a one-way nutrient flux;(Ⅲ)tumor-induced oxidative stress inflicts damage on myotubes,highlighting the detrimental effects of reactive oxygen species on muscle structure;(Ⅳ)KRAS-mutant cancer cells remodulate immune cell dynamics within the tumor environment,thereby reshaping host immunity.Together,these findings illuminate the intricate interplay between KRAS-mutant PC and skeletal muscle atrophy,mapping the pathophysiological framework that is crucial for understanding sarcopenia and related disorders.Conclusions:This comprehensive analysis advances our understanding of the complex etiology of cancer cachexia and stimulates the development of targeted therapeutic strategies.展开更多
Objective:To investigate the role of NF-κB in regulating myosin heavy chain(MyHC)content and muscle atrophy following laryngeal muscle denervation.Methods:Rats were divided into five groups:(1)recurrent laryngeal ner...Objective:To investigate the role of NF-κB in regulating myosin heavy chain(MyHC)content and muscle atrophy following laryngeal muscle denervation.Methods:Rats were divided into five groups:(1)recurrent laryngeal nerve injury(RLNI),(2)RLNI with NF-κB inhibition,(3)sham operation,(4)sham operation with injection,and(5)blank control.MyHC content and muscle atrophy in the thyroarytenoid(TA)and posterior cricoarytenoid(PCA)muscles were assessed over 14 days post-operation.Results:In the RLNI group,MyHC levels in TA muscle decreased progressively,with significant atrophy observed after 7 days.NF-κB inhibition delayed MyHC reduction until Day 11 and temporarily mitigated atrophy,though these effects diminished over time.In PCA muscle,MyHC levels showed a biphasic pattern,decreasing at Day 3,increasing on Days 7 and 11,and declining again by Day 14.PCA muscle atrophy progressed gradually,stabilizing by Day 11.NF-κB inhibition in PCA muscle led to delayed and less severe atrophy compared to the RLNI group,with higher MyHC levels observed on Days 3 and 7 but lower levels on Days 11 and 14.Conclusions:Within 14 days of denervation,the extent and timing of MyHC decline and muscle atrophy differ between TA muscle and PCA muscle.PCA muscle exhibits earlier changes than TA muscle.NF-κB inhibition temporarily delays muscle atrophy and MyHC loss but cannot sustain these effects long-term.展开更多
基金funded by research grants from the National Natural Science Foundation of China (32171135 and 32371168)。
文摘Purpose: This study aimed to explore the effects of a 10-week combined exercise regimen on immobilizationinduced muscle atrophy and elucidate the possible function of Protein arginine methyltransferase 1(Prmt1) in this process.Methods: 8-week-old male C57BL/6J mice were carried out combined exercise for 10 weeks. One week before the end of the intervention, mice underwent cast immobilization. Additionally, to investigate the potential mechanism in exercise-induced protection of skeletal muscle, mice in the exercise preconditioning group were administered TC-E-5003(an inhibitor of Prmt1 enzymatic activity). Exercise performance, muscle mass, and the cross-sectional area(CSA) of muscle fibers were analyzed. Besides, Prmt1 and Sestrin1(Sesn1) were either overexpressed or inhibited in C2C12 myotubes to elucidate the underlying mechanism.Results: Exercise preconditioning not only significantly improved muscle mass and motor ability in immobilized mice but also inhibited excessive activation of degradation pathways and enhanced protein synthesis. Importantly, Prmt1 mediated the protective effects of exercise preconditioning on muscle atrophy. Mechanistically,Prmt1 regulated the p38 mitogen-activated protein kinase(p38)/activating transcription factor 2(ATF2)pathway, which modulates Sesn1 expression. Sesn1 acts as a downstream of Prmt1 and ATF2, contributing to the myoblast differentiation and skeletal muscle regeneration through AMP-Activated protein kinase α2(AMPKα2)/transcriptional co-activator PPAR-γ co-activator-1 α(PGC-1α) signaling pathway.Conclusions: Taken together, our results highlighted the effectiveness of exercise preconditioning in preventing muscle atrophy via the Prmt1-Sesn1 pathway.
基金funded by research grant from National Natural Science Foundation of China(32171135).
文摘Resistance exercise has been confirmed to be important for maintaining muscle mass and function.However,despite considerable experimental studies,the underlying mechanisms still requires further investigation to be elucidated.Sestrin1 is a stress-inducible protein strongly associated with the occurrence and development of skeletal muscle dysfunction.Besides,oxidative stress is believed to be a major pathogenic mechanism in the development of skeletal muscle atrophy,whereas regular exercise training induces the endogenous antioxidative system and protects the body against adverse effects of oxidative stress.Nevertheless,whether Sestrin1 is involved in the amelioration of resistance exercise on muscle atrophy and the role of its antioxidant function in this process remains unknown.Here we show that six-week resistance exercise training significantly improved muscle function,muscle mass,and oxidative damage and maintained the level of Sestrin1 in dexamethasone-treated C57BL/6J mice.Mechanistically,Sestrin1 overexpression rescued protein degradation and oxidative stress in atrophied myotubes.Furthermore,an emerging regulator of cellular defense against toxic and oxidative insults,nuclear factor erythroid2–related factor 2(Nrf2)controls the basal and induced expression of an array of antioxidant response element–dependent genes to regulate the pathophysiological outcomes of oxidant exposure.In this study,we found that Nrf2 is a target of Sestrin1,and Nrf2 nuclear translocation is facilitated by Sestrin1.ML385(an Nrf2 inhibitor)treatment mitigated the regulatory effects of overexpression-Sestrin1.Therefore,Sestrin1 was involved in the process of resistance exercise against skeletal muscle atrophy,which may be closely related to its antioxidant capacity,revealing a potential therapeutic strategy for reducing the loss of skeletal muscle.
基金funded by Yunnan Youth Top-notch Talent Support Program(YNWR-QNBJ2018-173)Agricultural Joint project of Yunnan Provincial S&T Programs(202301BD070001-195)+2 种基金S&T project of Yunnan provincial finance(K212020001-01)supported by Yunnan Province Education Department’s Engineering Research Center of Eco-friendly Products from Yunnan Characteristic Edible FungiYunnan Province Yongsheng County Farmer Academician Technology service station.
文摘Muscle atrophy can be induced by high doses or prolonged use of glucocorticoids.Kaempferol(Kae)is a naturally occurring flavonoid with a variety of biological activities and the effect of Kae on dexamethasone(Dex)induced muscle atrophy in animals has not been elucidated.To explore this issue,the present experiments used a computationally assisted drug design scheme combining network pharmacology,molecular docking and in vivo experiments to investigate the mechanism of Kae against muscle atrophy.Network pharmacological analyses revealed 275 potential targets for Kae and 12294 potential targets for muscle atrophy,with a total of 228 crosstargets for Kae and muscle atrophy.GO and KEGG analyses were performed based on the protein-protein interaction(PPI)network of muscle atrophy and Kae component targets.The GO results showed that the biological processes were mainly related to the metabolic process of reactive oxygen species,and the response to oxidative stress;the cellular components were mainly focused on membrane microdomains,and membrane regions;the molecular functions mainly worked on phosphatase binding;and the KEGG pathway enrichment analyses identified the pathways of interaction between Kae and muscle atrophy.Finally,as verified by in vivo experiments,Kae may reduce the onset of muscle atrophy by activating the PI3K/AKT/m TOR/signalling pathway,inhibiting Foxo1/Foxo3 activity,and inhibiting downstream production of the ubiquitination 3 ligases Atrogin1 and Mu RF1;Kae also promotes the expression of NRF2/HO-1/KEAP1 signalling pathway,enhances muscle antioxidant capacity,inhibits the release of COX-2 and TNF-αinflammatory factors,and reduces the damage caused by oxidative stress and inflammatory factors to muscles.Therefore,there may be a synergistic effect of PI3K/AKT/m TOR and NRF2/HO-1/KEAP1 in Kae working together to prevent muscle atrophy.The binding energy and stability of Kae to potential targets were examined by molecular docking and molecular dynamics simulations,implying that Kae could be used for the prevention and treatment of muscle atrophy in patients.
基金supported by the funded project(HYZHX M05005)in the field of space medical experiments of manned spaceflight engineering.
文摘Objective:To evaluate the efficacy and safety of transcutaneous electrical acupoint stimulation(TEAS)for muscle atrophy in patients with immobilization after surgical fixation of foot and ankle fractures.Methods:This was a two-arm randomized controlled trial wherein 80 patients were recruited and divided into control(n=40)and intervention(n=40)groups.The control group received conventional orthopedic treatment,whereas the intervention group received TEAS and conventional treatment.The intervention group received TEAS 3 times a week for 30 min each time for 8 weeks.The primary out-comes were muscle thickness(MT)and cross-sectional area(CSA)of the rectus femoris and gastroc-nemius muscles,whereas the secondary outcome measure was echo intensity(EI).Data were collected before the fixation operations(baseline assessment)and 4 and 8 weeks after intervention.Results:Compared with baseline,the MT and CSA were reduced in both groups by the end of treatment,whereas EI increased in both groups.At week 4,the reduction in the rectus femoris CSA in the inter-vention group was significantly lower than that in the control group(P=0.02);however,the between-group differences in the MT and EI(all P>0.05)were not significant.No serious adverse events were observed in either group.Conclusion:Our study showed that TEAS can improve muscle atrophy by attenuating the decline in the muscle CSA.Because this was only a pilot trial,subsequent studies will need longer follow-ups and larger sample sizes.
基金Suzhou Science and Technology Development Planning Project,No.SYW2024048National Natural Science Foundation of China,No.81901933Major Natural Science Research Projects in Universities of Jiangsu Province,No.24KJA310007.
文摘Skeletal muscle atrophy results from disruptions in the growth and metabolism of striated muscle,leading to a reduction or loss of muscle fibers.This condition not only significantly impacts patients’quality of life but also imposes substantial socioeconomic burdens.The complex molecular mechanisms driving skeletal muscle atrophy contribute to the absence of effective treatment options.Recent advances in stem cell therapy have positioned it as a promising approach for addressing this condition.This article reviews the molecular mechanisms of muscle atrophy and outlines current therapeutic strategies,focusing on mesenchymal stem cells,induced pluripotent stem cells,and their derivatives.Additionally,the challenges these stem cells face in clinical applications are discussed.A deeper understanding of the regenerative potential of various stem cells could pave the way for breakthroughs in the prevention and treatment of muscle atrophy.
基金supported by the National Natural Science Foundation of China(82003447,32202023)the Natural Science Foundation of Shandong Province(ZR2021QC177)the Young Scholars Program of Shandong University(2018WLJH33,2018WLJH34)。
文摘Obesity is associated with skeletal muscle mass loss and physical dysfunction.Krill oil(KO)has been shown to be beneficial in human health.However,the effect of KO on obesity-induced skeletal muscle atrophy is still unclear.In this study,the male C57BL/6J mice were fed a high-fat diet(HFD)for 12 weeks to induce obesity,and then were intragastric administration with 400 mg/kg bw KO for an additional 6 weeks.The results showed that KO treatment reduced body weight,fat accumulation and serum pro-inflammatory cytokines in HFD-induced obese mice.Importantly,KO treatment attenuated skeletal muscle atrophy in HFD-fed mice,as evidenced by preserving skeletal muscle mass,average myofiber cross-sectional area and grip strength.KO administration also mitigated obesity-induced ectopic lipid deposition and inflammatory response in skeletal muscle.Additionally,KO treatment inhibited the transcriptional activities of nuclear factor-κB(NF-κB)p65 and forkhead box O 3a(FoxO3a),and then down-regulated muscle atrophy F-box(MAFbx)and muscle-specific RING finger protein 1(MuRF1)protein levels in skeletal muscle from HFD-fed mice.KO administration also improved obesity-induced impaired muscle protein synthesis via activating PI3K/Akt pathway.Furthermore,KO treatment enhanced muscle mitochondrial biogenesis in HFD-induced obese mice via activating PGC-1αpathway.Collectively,KO might be developed as a potential nutritional supplement for the prevention and treatment of obesity-induced skeletal muscle atrophy.
基金Guangdong Basic and Applied Basic Research Foundation,Grant/Award Number:2021A1515220030Hunan Provincial Clinical Medical Technology Innovation Guiding Project,Grant/Award Number:2020SK53307+2 种基金Hunan Provincial Health Commission,Grant/Award Number:20201902Natural Science Foundation of Hunan Province,Grant/Award Number:2020JJ8043Project of Hunan Provincial Health,Grant/Award Number:c2019133。
文摘Background:The aim of this study was to analyze the bi-directional causal relation-ship between lipid profile and characteristics related to muscle atrophy by using a bi-directional Mendelian randomization(MR)analysis.Methods:The appendicular lean mass(ALM),whole body fat-free mass(WBFFM)and trunk fat-free mass(TFFM)were used as genome-wide association study(GWAS)data for evaluating muscle mass;the usual walking pace(UWP)and low grip strength(LGS)were used as GWAS data for evaluating muscle strength;and the triglycerides(TG),total cholesterol(TC),high density lipoprotein cholesterol(HDL),low density lipo-protein cholesterol(LDL),apolipoprotein A-1(Apo A-1),and apolipoprotein B(Apo B)were used as GWAS data for evaluating lipid profile.For specific investigations,we mainly employed inverse variance weighting for causal estimation and MR-Egger for pleiotropy analysis.Results:MR results showed that the lipid profile predicted by genetic variants was negatively correlated with muscle mass,positively correlated with UWP,and was not causally correlated with LGS.On the other hand,the muscle mass predicted by genetic variants was negatively correlated with lipid profile,the UWP predicted by genetic variants was mainly positively correlated with lipid profile,while the LGS pre-dicted by genetic variants had no relevant causal relationship with lipid profile.Conclusions:Findings of this MR analysis suggest that hyperlipidemia may affect muscle mass and lead to muscle atrophy,but has no significant effect on muscle strength.On the other hand,increased muscle mass may reduce the incidence of dyslipidemia.
基金funded by the National Basic Research Program of China(973 Program),No.2014CB542201the National High Technology Research and Development Program of China(863 Program),No.SS2015AA020501the National Natural Science Foundation of China(General Program),No.31571235,31771322,31671248,31571236,31271284,31171150,81171146,31471144,30971526,31100860,31040043,31371210,and 81372044
文摘Delay of axon regeneration after peripheral nerve injury usually leads to progressive muscle atrophy and poor functional recovery. The Wnt/β-catenin signaling pathway is considered to be one of the main molecular mechanisms that lead to skeletal muscle atrophy in the elderly. We hold the hypothesis that the innervation of target muscle can be promoted by accelerating axon regeneration and decelerating muscle cell degeneration so as to improve functional recovery of skeletal muscle following peripheral nerve injury. This process may be associated with the Wnt/β-catenin signaling pathway. Our study designed in vitro cell models to simulate myelin regeneration and muscle atrophy. We investigated the effects of SB216763, a glycogen synthase kinase 3 beta inhibitor, on the two major murine cell lines RSC96 and C2C12 derived from Schwann cells and muscle satellite cells. The results showed that SB216763 stimulated the Schwann cell migra- tion and myotube contraction. Quantitative polymerase chain reaction results demonstrated that myelin related genes, myelin associated glycoprotein and cyclin-D1, muscle related gene myogenin and endplate-associated gene nicotinic acetylcholine receptors levels were stimulated by SB216763. Immunocytochemical staining revealed that the expressions of ^-catenin in the RSC96 and C2C12 cytosolic and nuclear compartments were increased in the SB216763-treated cells. These findings confirm that the glycogen synthase kinase 3 beta in- hibitor, SB216763, promoted the myelination and myotube differentiation through the Wnt/β-catenin signaling pathway and contributed to nerve remyelination and reduced denervated muscle atrophy after peripheral nerve injury.
基金supported by grants from the National Key Research and Development Project(2020YFA0803800 to JL,2018YFE0113500 to JX)National Natural Science Foundation of China(82020108002 and 81911540486 to JX)+2 种基金Innovation Program of Shanghai Municipal Education Commission(2017-01-07-00-09-E00042 to JX)Science and Technology Commission of Shanghai Municipality(20DZ2255400 and 18410722200 to JX)the“Dawn”Program of the Shanghai Education Commission(19SG34 to JX).
文摘Background:Exercise is beneficial for muscle atrophy.Peroxisome proliferator-activated receptor gamma(PPARγ) and microRNA-29 b(miR-29 b) have been reported to be responsible for angiotensinⅡ(AngⅡ)-induced muscle atrophy.However,it is unclear whether exercise can protect AngⅡ-induced muscle atrophy by targeting PPARγ/miR-29 b.Methods:Skeletal muscle atrophy in both the control group and the run group was established by AngⅡ infusion;after 1 week of exercise training,the mice were sacrificed,and muscle weight was determined.Myofiber size was measured by hematoxylin-eosin and wheat-germ agglutinin staining.Apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling staining.The expression level of muscle atrogenes,including F-box only protein 32(FBXO32,also called Atrogin-1) and muscle-specific RING-finger 1(MuRF-1),the phosphorylation level of protein kinase B(PKB,also called AKT)/forkhead box 03 A(FOX03 A)/mammalian target of rapamycin(mTOR) pathway proteins,the expression level of PPARγ and apoptosis-related proteins,including B-cell lymphoma-2(Bcl-2),Bcl-2-associated X(Bax),cysteine-aspartic acid protease 3(caspase-3),and cleaved-caspase-3,were determined by western blot.The expression level of miR-29 b was checked by reversetranscription quantitative polymerase chain reaction.A PPARγ inhibitor(T0070907) or adeno-associated virus serotype-8(AAV8)-mediated miR-29 b overexpression was used to demonstrate whether PPARγ activation or miR-29 b inhibition mediates the beneficial effects of exercise in AngⅡ-induced muscle atrophy.Results:Exercise can significantly attenuate AngⅡ-induced muscle atrophy,which is demonstrated by increased skeletal muscle weight,cross-sectional area of myofiber,and activation of AKT/mTOR signaling and by decreased atrogenes expressions and apoptosis.In AngⅡ-induced muscle atrophy mice models,PPARγ was elevated whereas miR-29 b was decreased by exercise.The protective effects of exercise in AngⅡ-induced muscle atrophy were inhibited by a PPARγ inhibitor(T0070907) or adeno-associated virus serotype-8(AAV8)-mediated miR-29 b overexpression.Conclusion:Exercise attenuates AngⅡ-induced muscle atrophy by activation of PPARγ and suppression of miR-29 b.
基金Project supported by the Japan Society for the Promotion of Science(JSPS)KA-KENHI(Nos.20500578 and 17K01765)the Ministry of Education,Culture,Sports,Science and Technology(MEXT)-Supported Program for the Strategic Research Foundation at Private Universities
文摘We examined the effect of a combination of astaxanthin （AX） supplementation, repeated heat stress, and intermittent reloading （IR） on satellite cells in unloaded rat soleus muscles. Forty-nine male Wistar rats （8-week-old） were divided into control, hind-limb unweighting （HU）, IR during HU, IR with AX supplementation, IR with repeated heat stress （41.0-41.5 ℃ for 30 min）, and IR with AX supplementation and repeated heat stress groups. After the experimental period, the antigravitational soleus muscle was analyzed using an immunohistochemical technique. Our results revealed that the combination of dietary AX supplementation and heat stress resulted in protection against disuse muscle atrophy in the soteus muscle. This protective effect may be partially due to a higher satellite cell number in the atrophied soleus muscle in the IR/AX/heat stress group compared with the numbers found in the other groups. We concluded that the combination treatment with dietary AX supplementation and repeated heat stress attenuates soleus muscle atrophy, in part by increasing the number of satellite cells.
基金supported by grants from the National Institutes of Health,USA(No.K08 AR060164-01A)Department of Defense,USA(Nos.W81XWH-16-1-0725 and W81XWH-19-1-0773)in addition to institutional support from the Pennsylvania State University College of Medicine。
文摘We recently demonstrated a repurposing beneficial effect of 4-aminopyridine(4-AP),a potassium channel blocker,on functional recove ry and muscle atrophy after sciatic nerve crush injury in rodents.However,this effect of 4-AP is unknown in nerve transection,gap,and grafting models.To evaluate and compare the functional recovery,nerve morphology,and muscle atrophy,we used a novel stepwise nerve transection with gluing(STG),as well as 7-mm irreparable nerve gap(G-7/0)and 7-mm isografting in 5-mm gap(G-5/7)models in the absence and presence of 4-AP treatment.Following surgery,sciatic functional index was determined wee kly to evaluate the direct in vivo global motor functional recovery.After 12 weeks,nerves were processed for whole-mount immunofluorescence imaging,and tibialis anterior muscles were harvested for wet weight and quantitative histomorphological analyses for muscle fiber crosssectional area and minimal Feret's diameter.Average post-injury sciatic functional index values in STG and G-5/7 models were significantly greater than those in the G-7/0 model.4-AP did not affect the sciatic functional index recovery in any model.Compared to STG,nerve imaging revealed more misdirected axons and distorted nerve architecture with isografting.While muscle weight,cross-sectional area,and minimal Feret's diameter were significantly smaller in G-7/0 model compared with STG and G-5/7,4-AP treatment significantly increased right TA muscle mass,cross-sectional area,and minimal Feret's diameter in G-7/0 model.These findings demonstrate that functional recovery and muscle atrophy after peripheral nerve injury are directly related to the intervening nerve gap,and 4-AP exerts diffe rential effects on functional recove ry and muscle atrophy.
文摘Objective To compare the cross section area (CSA) and the immunoreactivity of conjugated ubiquitin in soleus extrafusal and intrafusal fibers after simulated microgravity and to demonstrate the role of muscle spindle in muscle atrophy induced by simulated microgravity. Methods The immunohistochemical technique (ABC) and image analysis were used to assess the conjugated ubiquitin immunostaining and the cross sectional area of intrafusal and extrafusal fibers of soleus in simulated microgravity rats. Results ①Tail suspension caused a progressive loss of soleus mass. Mean fiber CSA of extrafusal fibers were (7±2)%, (21±4)% and (32±7)% smaller after 3 days, 7 days and 14 days suspension, respectively. While the CAS of intrafusal fibers (bag + chain fibers) were (14±3)% ( P < 0.05 ), (30±7)% ( P < 0.01 ) and (44±10)% ( P < 0.01 ) smaller after 3 days, 7 days and 14 days suspension. ② The immunoreactivity of conjugated ubiquitin both in extrafusal and intrafusal fibers increased after tail suspension. The immunoreactivity of intrafusal fibers increased 1 day after suspension and reached the hightest level at 3 days after tail suspension. The immunoreactivity of extrafusal fibers increased after 3 days suspension and reached the highest level after 7 days tail suspension, which was lower than that in intrafusal fibers after 3 days tail suspension. Conclusion These results suggest that soleus atrophy of intrafusal fibers caused by tail suspension is earlier and more severe than that in extrafusal fibers.
基金supported by the National Natural Science Foundation of China(Grant No.32200940)Science and Technology Bureau of Nantong(Grant Nos.JC2020101,JC2021085)Municipal Health Commission of Nantong(Grant No.MA2020019).
文摘Denervation-induced skeletal muscle atrophy can potentially cause the decline in the quality of life of patients and an increased risk of mortality.Complex pathophysiological mechanisms with dynamic alterations have been documented in skeletal muscle atrophy resulting from innervation loss.Hence,an in-depth comprehension of the key mechanisms and molecules governing skeletal muscle atrophy at varying stages,along with targeted treatment and protection,becomes essential for effective atrophy management.Our preliminary research categorizes the skeletal muscle atrophy process into four stages using microarray analysis.This review extensively discusses the pathways and molecules potentially implicated in regulating the four stages of denervation and muscle atrophy.Notably,drugs targeting the reactivare oxygen species stage and the inflammation stage assume critical roles.Timely intervention during the initial atrophy stages can expedite protection against skeletal muscle atrophy.Additionally,pharmaceutical intervention in the ubiquitin-proteasome pathway associated with atrophy and autophagy lysosomes can effectively slow down skeletal muscle atrophy.Key molecules within this stage encompass MuRF1,MAFbx,LC3II,p62/SQSTM1,etc.This review also compiles a profile of drugs with protective effects against skeletal muscle atrophy at distinct postdenervation stages,thereby augmenting the evidence base for denervation-induced skeletal muscle atrophy treatment.
基金National Natural Science Foundation of China(No.81960417)Guangxi Natural Science Foundation Project(No.2018GXNSFAA050033)+1 种基金Guangxi Science and Technology Key R&D Project(No.Guike AB20159027)Guangxi Natural Science Foundation Youth Fund Project(No.2022GXNSFBA035545)。
文摘Objective:To find the key targets of muscle atrophy after spinal cord injury(SCI)were excavated,to construct the lncRNA-miRNA-mRNA regulatory network based on bioinformatics analysis,and to verify the expression changes of key regulatory networks in muscle atrophy after SCI by animal experiments,so as to seek new research directions for the pathogenesis and treatment of muscle atrophy after SCI.Methods:The GSE21497 data set was downloaded from the GEO database for differential expression gene screening and WGCNA treatment.Combined with the online prediction database,key mRNAs were screened out.GO and KEGG enrichment analyses of key mRNAs were performed using the DAVID database to construct the lncRNA-miRNA-mRNA regulatory network.The key regulatory genes were selected and then verified by RT-qPCR.Results:A total of 1405 differentially expressed genes were screened,and 30 key mRNAs were predicted by the WGCNA and online database.GO and KEGG enrichment analyses showed that it was mainly enriched in the functions of neuron regeneration,protection,signal transmission,the HIF signaling pathway,PD-L1 expression and the PD-1 checkpoint pathway.Four key regulatory networks were identified(LINC00410/miR-17-5p/KCNK10,LINC00410/miR-17-5p/PCDHA3,LINC00410/miR-20b-5p/KCNK10,LINC00410/miR-20b-5p/PCDHA3).The results of RT-qPCR showed that,compared with the control group,the expression of miR-17-5p and miR-20b-5p in the observation group increased,and the expression of KCNK10 and PCDHA3 decreased.Conclusions:MiR-17-5p,miR-20b-5p,KCNK10,and PCDHA3 may play an important regulatory role in the regeneration,protection,and signal transmission of neurons,which is expected to become a new target for the diagnosis and treatment of muscle atrophy after SCI.
基金the Foundation of State Key Laboratory of Component-based Chinese Medicine,No.CBCM2023107National Natural Science Foundation of China,No.81901853Specially Funded Scientific Research Project of the Fourth Affiliated Hospital of Harbin Medical University,No.HYDSYTB202126.
文摘Over the course of several decades,robust research has firmly established the significance of mitochondrial pathology as a central contributor to the onset of skeletal muscle atrophy in individuals with diabetes.However,the specific intricacies governing this process remain elusive.Extensive evidence highlights that individuals with diabetes regularly confront the severe consequences of skeletal muscle degradation.Deciphering the sophisticated mechanisms at the core of this pathology requires a thorough and meticulous exploration into the nuanced factors intricately associated with mitochondrial dysfunction.
基金supported by the Natural Science Foundation of China(Grant No.32071517,82072106)the Natural Science Basic Research Plan in Shaanxi Province of China(Grant No.2020JM-100).
文摘As a key coordinator of metabolism,AMP-activated protein kinase(AMPK)is vitally involved in skeletal muscle maintenance.AMPK exerts its cellular effects through its function as a serine/threonine protein kinase by regulating many downstream targets and plays important roles in the development and growth of skeletal muscle.AMPK is activated by phosphorylation and exerts its function as a kinase in many processes,including synthesis and degradation of proteins,mitochondrial biogenesis,glucose uptake,and fatty acid and cholesterol metabolism.Skeletal muscle atrophy is a result of various diseases or disorders and is characterized by a decrease in muscle mass.The pathogenesis and therapeutic strategies of skeletal muscle atrophy are still under investigation.In this review,we discuss the role of AMPK in skeletal muscle metabolism and atrophy.We also discuss targeting AMPK for skeletal muscle treatment,including exercise,AMPK activators including 5-amino-4-imidazolecarboxamide ribonucleoside and metformin,and low-level lasers.These studies show the important roles of AMPK in regulating muscle metabolism and function;thus,the treatment of skeletal muscle atrophy needs to take into account the roles of AMPK.
文摘The depressed protein synthetic response,a phenomenon termed anabolic resistance,has been shown to be involved in muscle wasting induced by cancer cachexia.Moreover,a positive relationship between the protein synthetic rate and intracellular glutamine(GLN)concentration has been found in skeletal muscles.This study investigated the effects of neuromuscular electrical stimulation(ES)and GLN administration on muscle wasting and GLN metabolism in colon-26(C-26)tumor-bearing mice.CD2F1 mice were divided into 8 groups:control(CNT),CNT+ES,CNT+GLN,CNT+ES+GLN,C-26,C-26+ES,C-26+GLN,C-26+ES+GLN.Cancer cachexia was induced by subcutaneous injection of C-26 cells and developed for four weeks.ES was performed on the left plantar flexor muscles every other day,and GLN(1 g/kg)was administered daily intraperitoneally starting one day after the C-26 injection.Tumor-free body mass and fast-twitch gastrocnemius(Gas)muscle weight were lower in the C-26 group than in the CNT group(-19%and-17%,respectively).Neither ES training nor GLN administration,alone or in combination,ameliorated the loss of Gas muscle weight in the C-26 mice.However,ES training in combination with GLN administration inhibited the increased expression of GLN synthetase(GS)in the C-26 muscles.Thus,it is likely that GLN plays a critical role in muscle protein metabolism and,therefore,can be targeted as a tentative treatment of cancer cachexia.
基金supported by the Startup Fund for Scientific Research of Fujian Medical University(no.2021QH1114)the National Natural Science Foundation of China(no.8217-2953)the National Natural Science Foundation of Fujian(2023Y9052).
文摘Concomitant exotropia is a common chronic eye disease characterized by abnormal movement of the extraocular muscles caused by a functional imbalance of the nerves related to the movement of the extraocular muscles.This study revealed that the expression levels of S-100β and the muscle area decreased in the extraocular muscles of patients with concomitant exotropia,whereas the expression of calcitonin gene-related peptide(CGRP)increased.In CGRP-KO rats,low expression of CGRP was positively correlated with muscle atrophy.Moreover,the expression level of muscle cells,which are fast myosin heavy chain positive and slow myosin positive in CGRP-KO rats,was lower than that in the control group.Drug intervention experiments further confirmed the inhibitory effect of CGRP on muscle atrophy.The level of apoptosis in the extraocular muscles of CGRP-KO rats was significantly greater than that in the control group(P<0.05),and the phosphorylation level of AKT/CREB in the extraocular muscles of patients with concomitant exotropia was greater than that in the control group.The increased expression of CGRP in the extraocular muscles of patients with concomitant exotropia may inhibit the apoptosis of extraocular muscle cells through the AKT/CREB signaling pathway and participate in the protective effect of the extraocular muscles in concomitant exotropia.
基金supported by grants from the Shanghai Municipal Health Commission Health Industry Clinical Research Project(No.201940019)National Natural Science Foundation of China(Nos.82273382,82272929,82103409,81972218,81972257,and 81827807)+5 种基金Shanghai ShenKang Hospital Development Centre Project(No.SHDC2020CR2017B)Program of Shanghai Academic/Technology Research Leader(No.23XD1400600)China Postdoctoral Science Foundation(No.2021M690037)Shanghai Sailing Program(No.21YF1407100),the Open Fund of the Key Laboratory of Hepatosplenic Surgery,Ministry of Education,Harbin,China(No.GPKF202302)Beijing Xisike Clinical Oncology Research Foundation(Nos.Y-2022METAZQN-0003,Y-HR2022MS-0251,and Y-HR2022QN-0085)Science and Technology Planning Project of Yunnan Province(No.202305AF150148).
文摘Background and Objective:Cachexia-induced skeletal muscle atrophy is a critical manifestation in Kirsten rat sarcoma viral oncogene homologue(KRAS)-mutant pancreatic cancer(PC)patients,predominantly characterized by a shift in metabolic equilibrium towards catabolism that accelerates protein degradation in myofibers and leads to muscle atrophy.This metabolic reprogramming not only supports tumor growth but also precipitates energy depletion in skeletal muscle tissues.Exploring these mechanisms reveals potential therapeutic targets in the metabolic and proteolytic pathways associated with KRAS-mutant PC.Methods:A comprehensive search for literature was conducted in PubMed,Web of Science,Google Scholar and other search engines up to May 21st,2024.Studies on PC models and patients were included.Key Content and Findings:The crosstalk between KRAS-mutant PC and skeletal muscle atrophy can be categorized into four principal domains:(I)KRAS-driven metabolic reprogramming in cancer cells leads to the depletion of muscle energy reserves,thereby influencing the reallocation of myofiber energy towards fueling cancer cell;(Ⅱ)KRAS-mutant cancer cells rely on nutrient-scavenging pathways,resulting in altered cytokine profiles,increased ubiquitin mRNA expression and autophagy-lysosome pathway,which facilitate myotube degradation and inhibit muscle regeneration,thereby disrupting muscular homeostasis and causing a one-way nutrient flux;(Ⅲ)tumor-induced oxidative stress inflicts damage on myotubes,highlighting the detrimental effects of reactive oxygen species on muscle structure;(Ⅳ)KRAS-mutant cancer cells remodulate immune cell dynamics within the tumor environment,thereby reshaping host immunity.Together,these findings illuminate the intricate interplay between KRAS-mutant PC and skeletal muscle atrophy,mapping the pathophysiological framework that is crucial for understanding sarcopenia and related disorders.Conclusions:This comprehensive analysis advances our understanding of the complex etiology of cancer cachexia and stimulates the development of targeted therapeutic strategies.
基金Funded by National Natural Science Foundation of China(82171124)Beijing Municipal Natural Science Foundation(7172051)。
文摘Objective:To investigate the role of NF-κB in regulating myosin heavy chain(MyHC)content and muscle atrophy following laryngeal muscle denervation.Methods:Rats were divided into five groups:(1)recurrent laryngeal nerve injury(RLNI),(2)RLNI with NF-κB inhibition,(3)sham operation,(4)sham operation with injection,and(5)blank control.MyHC content and muscle atrophy in the thyroarytenoid(TA)and posterior cricoarytenoid(PCA)muscles were assessed over 14 days post-operation.Results:In the RLNI group,MyHC levels in TA muscle decreased progressively,with significant atrophy observed after 7 days.NF-κB inhibition delayed MyHC reduction until Day 11 and temporarily mitigated atrophy,though these effects diminished over time.In PCA muscle,MyHC levels showed a biphasic pattern,decreasing at Day 3,increasing on Days 7 and 11,and declining again by Day 14.PCA muscle atrophy progressed gradually,stabilizing by Day 11.NF-κB inhibition in PCA muscle led to delayed and less severe atrophy compared to the RLNI group,with higher MyHC levels observed on Days 3 and 7 but lower levels on Days 11 and 14.Conclusions:Within 14 days of denervation,the extent and timing of MyHC decline and muscle atrophy differ between TA muscle and PCA muscle.PCA muscle exhibits earlier changes than TA muscle.NF-κB inhibition temporarily delays muscle atrophy and MyHC loss but cannot sustain these effects long-term.
