Systematic bone and muscle loss is a complex metabolic disease,which is frequently linked to gut dysfunction,yet its etiology and treatment remain elusive.While probiotics show promise in managing diseases through mic...Systematic bone and muscle loss is a complex metabolic disease,which is frequently linked to gut dysfunction,yet its etiology and treatment remain elusive.While probiotics show promise in managing diseases through microbiome modulation,their therapeutic impact on gut dysfunction-induced bone and muscle loss remains to be elucidated.Employing dextran sulfate sodium(DSS)-induced gut dysfunction model and wide-spectrum antibiotics(ABX)-treated mice model,our study revealed that gut dysfunction instigates muscle and bone loss,accompanied by microbial imbalances.Importantly,Bifidobacterium animalis subsp.lactis A6(B.lactis A6)administration significantly ameliorated muscle and bone loss by modulating gut microbiota composition and enhancing butyrate-producing bacteria.This intervention effectively restored depleted butyrate levels in serum,muscle,and bone tissues caused by gut dysfunction.Furthermore,butyrate supplementation mitigated musculoskeletal loss by repairing the damaged intestinal barrier and enriching beneficial butyrate-producing bacteria.Importantly,butyrate inhibited the NF-κB pathway activation,and reduced the secretion of corresponding inflammatory factors in T cells.Our study highlights the critical role of dysbiosis in gut dysfunction-induced musculoskeletal loss and underscores the therapeutic potential of B.lactis A6.These discoveries offer new microbiome directions for translational and clinical research,providing promising strategies for preventing and managing musculoskeletal diseases.展开更多
Current therapeutic approaches for volumetric muscle loss(VML)face challenges due to limited graft availability and insufficient bioactivities.To overcome these limitations,tissue-engineered scaffolds have emerged as ...Current therapeutic approaches for volumetric muscle loss(VML)face challenges due to limited graft availability and insufficient bioactivities.To overcome these limitations,tissue-engineered scaffolds have emerged as a promising alternative.In this study,we developed aligned ternary nanofibrous matrices comprised of poly(lactide-co-ε-caprolactone)integrated with collagen and Ti_(3)C_(2)T_(x)MXene nanoparticles(NPs)(PCM matrices),and explored their myogenic potential for skeletal muscle tissue regeneration.The PCM matrices demonstrated favorable physicochemical properties,including structural uniformity,alignment,microporosity,and hydrophilicity.In vitro assays revealed that the PCM matrices promoted cellular behaviors and myogenic differentiation of C2C12 myoblasts.Moreover,in vivo experiments demonstrated enhanced muscle remodeling and recovery in mice treated with PCM matrices following VML injury.Mechanistic insights from next-generation sequencing revealed that MXene NPs facilitated protein and ion availability within PCM matrices,leading to elevated intracellular Ca^(2+)levels in myoblasts through the activation of inducible nitric oxide synthase(i NOS)and serum/glucocorticoid regulated kinase 1(SGK1),ultimately promoting myogenic differentiation via the m TOR-AKT pathway.Additionally,upregulated i NOS and increased NO–contributed to myoblast proliferation and fiber fusion,thereby facilitating overall myoblast maturation.These findings underscore the potential of MXene NPs loaded within highly aligned matrices as therapeutic agents to promote skeletal muscle tissue recovery.展开更多
Muscle flaps must have a strong vascular network to support a large tissue volume and ensure successful engraftment.We developed porcine stomach musculofascial flap matrix(PDSF)comprising extracellular matrix(ECM)and ...Muscle flaps must have a strong vascular network to support a large tissue volume and ensure successful engraftment.We developed porcine stomach musculofascial flap matrix(PDSF)comprising extracellular matrix(ECM)and intact vasculature.PDSF had a dominant vascular pedicle,microcirculatory vessels,a nerve network,well-retained 3-dimensional(3D)nanofibrous ECM structures,and no allo-or xenoantigenicity.In-depth proteomic analysis demonstrated that PDSF was composed of core matrisome proteins(e.g.,collagens,glycoproteins,proteoglycans,and ECM regulators)that,as shown by Gene Ontology term enrichment analysis,are functionally related to musculofascial biological processes.Moreover,PDSFhuman adipose-derived stem cell(hASC)synergy not only induced monocytes towards IL-10producing M2 macrophage polarization through the enhancement of hASCs’paracrine effect but also promoted the proliferation and interconnection of both human skeletal muscle myoblasts(HSMMs)and human umbilical vein endothelial cells(HUVECs)in static triculture conditions.Furthermore,PDSF was successfully prevascularized through a dynamic perfusion coculture of hASCs and HUVECs,which integrated with PDSF and induced the maturation of vascular networks in vitro.In a xenotransplantation model,PDSF demonstrated myoconductive and immunomodulatory properties associated with the predominance of M2 macrophages and regulatory T cells.In a volumetric muscle loss(VML)model,prevascularized PDSF augmented neovascularization and constructive remodeling,which was characterized by the predominant infiltration of M2 macrophages and significant musculofascial tissue formation.These results indicate that hASCs’integration with PDSF enhances the cells’dual function in immunomodulation and angiogenesis.Owing in part to this PDSF-hASC synergy,our platform shows promise for vascularized muscle flap engineering for VML reconstruction.展开更多
Volumetric muscle loss(VML)injuries characterized by critical loss of skeletal muscle tissues result in severe functional impairment.Current treatments involving use of muscle grafts are limited by tissue availability...Volumetric muscle loss(VML)injuries characterized by critical loss of skeletal muscle tissues result in severe functional impairment.Current treatments involving use of muscle grafts are limited by tissue availability and donor site morbidity.In this study,we designed and synthesized an implantable glycosaminoglycan-based hydrogel system consisting of thiolated hyaluronic acid(HA)and thiolated chondroitin sulfate(CS)cross-linked with poly(ethylene glycol)diacrylate to promote skeletal muscle regeneration of VML injuries in mice.The HA-CS hydrogels were optimized with suitable biophysical properties by fine-tuning degree of thiol group substitution to support C2C12 myoblast proliferation,myogenic differentiation and expression of myogenic markers MyoD,MyoG and MYH8.Furthermore,in vivo studies using a murine quadriceps VML model demonstrated that the HA-CS hydrogels supported integration of implants with the surrounding host tissue and facilitated migration of Pax7+satellite cells,de novo myofiber formation,angiogenesis,and innervation with minimized scar tissue formation during 4-week implantation.The hydrogel-treated and autograft-treated mice showed similar functional improvements in treadmill performance as early as 1-week post-implantation compared to the untreated groups.Taken together,our results demonstrate the promise of HA-CS hydrogels as regenerative engineering matrices to accelerate healing of skeletal muscle injuries.展开更多
Volumetric muscle loss(VML)refers to a composite,en bloc loss of skeletal muscle mass resulting in functional impairment.These injuries normally heal with excessive fibrosis,minimal skeletal muscle regeneration,and po...Volumetric muscle loss(VML)refers to a composite,en bloc loss of skeletal muscle mass resulting in functional impairment.These injuries normally heal with excessive fibrosis,minimal skeletal muscle regeneration,and poor functional recovery.Functional muscle transfer is a treatment option for some patients but is limited both by the degree of functional restoration as well as donor site morbidity.As such,new therapeutic options are necessary.De novo regeneration of skeletal muscle,by way of tissue engineering,is an emerging strategy to treat VML.This review evaluates available scaffolds for promoting skeletal muscle regeneration and functional recovery following VML.The use of growth factors and stem cell therapies,which may augment scaffold integration and skeletal muscle reconstitution,are also discussed.Regenerative medicine with the use of scaffolds is a promising area in skeletal muscle reconstruction and VML treatment.展开更多
Obesity affects over 1 billion people worldwide and is linked to more than 230 health complications,with cardiovascular disease being a leading cause of mortality.Losing 5%-10%of body weight is considered clinically s...Obesity affects over 1 billion people worldwide and is linked to more than 230 health complications,with cardiovascular disease being a leading cause of mortality.Losing 5%-10%of body weight is considered clinically significant for improving health.This weight loss can be achieved through pharmacotherapy,including glucagon-like peptide 1(GLP-1)receptor agonists,GLP-1/glucosedependent insulinotropic peptide dual receptor agonists,and GLP-1/glucosedependent insulinotropic peptide/glucagon triple receptor agonists(such as semaglutide,tirzepatide,and retatrutide,respectively).While much of the weight loss comes from fat mass,these treatments also result in the loss of lean mass,including muscle.This loss of muscle may contribute to difficulties in maintaining weight over the long term and can lead to sarcopenia.Therefore,the focus of new anti-obesity treatments should be primarily on reducing fat mass while minimizing the loss of muscle mass,ideally promoting muscle gain.Research focusing on human myocytes has identified more than 600 myokines associated with muscle contraction,which may play a crucial role in preserving both muscle mass and function.We explored the potential of new anti-obesity agents and their combinations with incretin-based therapies to achieve these outcomes.Further studies are needed to better understand the functional implications of lean mass expansion during weight loss and weight maintenance programs.展开更多
We previously demonstrated that lipopolysaccharide(LPS)injection-induced immune stress could impair muscle growth in weaned piglets,but the precise mechanisms behind this remain elusive.Here,we found that chronic immu...We previously demonstrated that lipopolysaccharide(LPS)injection-induced immune stress could impair muscle growth in weaned piglets,but the precise mechanisms behind this remain elusive.Here,we found that chronic immune stress induced by LPS resulted in a significant reduction of 36.86%in the total muscle mass of piglets at 5 d post-treatment compared with the control group.At 1 d,prior to muscle mass loss,multiple alterations were noted in response to LPS treatment.These included a reduction in the abundance of Bacteroidetes,an increase in serum concentrations of pro-inflammatory cytokines,compromised mitochondrial morphology,and an upregulation in the expression of dynamin-related protein 1(Drp1),a critical protein involved in mitochondrial fission.We highlight a strong negative correlation between Bacteroidetes abundance and the levels of serum pro-inflammatory cytokines,corroborated by in vivo intervention strategies in the musculature of both pig and mouse models.Mechanistically,the effects of Bacteroidetes on inflammation and muscle mass loss may involve the signaling pathway of the tauro-β-muricholic acid-fibroblast growth factor 15.Furthermore,the induction of overexpression of inflammatory cytokines,achieved without LPS treatment through oral administration of recombinant human IL-6(rh IL-6),led to increased levels of circulating cytokines,subsequently causing a decrease in muscle mass.Notably,pre-treatment with Mdivi-1,an inhibitor of Drp-1,markedly attenuated the LPS-induced elevation in reactive oxygen species levels and rescued the associated decline in muscle mass.Collectively,these data indicate that LPS-induced muscle mass loss was linked to the reduction of Bacteroidetes abundance,increased inflammation,and the disruption of mitochondrial morphology.These insights offer promising avenues for the identification of potential therapeutic targets aimed at mitigating muscle mass loss.展开更多
Nicotinamide adenine dinucleotide(NADH)is a cofactor that serves to shuttle electrons during metabolic processes such as glycolysis,the tricarboxylic acid cycle,and oxidative phosphorylation(OXPHOS).NADH is autofluore...Nicotinamide adenine dinucleotide(NADH)is a cofactor that serves to shuttle electrons during metabolic processes such as glycolysis,the tricarboxylic acid cycle,and oxidative phosphorylation(OXPHOS).NADH is autofluorescent,and itsfluorescence lifetime can be used to infer metabolic dynamics in living cells.Fiber-coupled time-correlated single photon counting(TCSPC)equipped with an implantable needle probe can be used to measure NADH lifetime in vivo,enabling investigation of changing metabolic demand during muscle contraction or tissue regeneration.This study illustrates a proof of concept for point-based,minimally-invasive NADHfluorescence lifetime measurement in vivo.Volumetric muscle loss(VML)injuries were created in the left tibialis anterior(TA)muscle of male Sprague Dawley rats.NADH lifetime measurements were collected before,during,and after a 30 s tetanic contraction in the injured and uninjured TA muscles,which was subsequently-t to a biexponential decay model to yield a metric of NADH utilization(cytoplasmic vs protein-bound NADH,the A11/A22 ratio).On average,this ratio was higher during and after contraction in uninjured muscle compared to muscle at rest,suggesting higher levels of free NADH in contracting and recovering muscle,indicating increased rates of glycolysis.In injured muscle,this ratio was higher than uninjured muscle overall but decreased over time,which is consistent with current knowledge of inflammatory response to injury,suggesting tissue regeneration has occurred.These data suggest that-ber-coupled TCSPC has the potential to measure changes in NADH binding in vivo in a minimally invasive manner that requires further investigation.展开更多
Rheumatoid arthritis(RA)is a prevalent and debilitating inflammatory disease that significantly impairs functional capacity and quality of life.RA accelerates musculoskeletal aging,leading to complications such as mus...Rheumatoid arthritis(RA)is a prevalent and debilitating inflammatory disease that significantly impairs functional capacity and quality of life.RA accelerates musculoskeletal aging,leading to complications such as muscle degeneration and sarcopenia.Recent research has identified myopenia as a condition of significant muscle loss associated with illness,distinct from the muscle wasting seen in other chronic diseases like cancer cachexia or heart failure.In RA,myopenia is characterized by muscle depletion without concurrent significant fat loss,and it can affect individuals of all ages.While inflammation plays a central role,it is not the sole factor contributing to the high incidence of muscle wasting in RA.In subsequent discussions,secondary sarcopenia will be considered alongside myopenia,as both involve muscle wasting decline primarily due to disease.This review summarizes recent findings on the impact of RA-related myopenia and secondary sarcopenia on functional capacity,explores its underlying mechanisms,and discusses contemporary strategies to mitigate the process of musculoskeletal aging in RA patients.展开更多
Polytrauma with significant bone and volumetric muscle loss presents substantial clinical challenges.Although immune responses significantly influence fracture healing post-polytrauma,the cellular and molecular underp...Polytrauma with significant bone and volumetric muscle loss presents substantial clinical challenges.Although immune responses significantly influence fracture healing post-polytrauma,the cellular and molecular underpinnings of polytrauma-induced immune dysregulation require further investigation.While previous studies examined either injury site tissue or systemic tissue(peripheral blood),our study uniquely investigated both systemic and local immune cells at the same time to better understand polytrauma-induced immune dysregulation and associated impaired bone healing.Using single-cell RNA sequencing(scRNA-seq)in a rat polytrauma model,we analyzed blood,bone marrow,and the local defect soft tissue to identify potential cellular and molecular targets involved in immune dysregulation.We identified a trauma-associated immunosuppressive myeloid(TIM)cell population that drives systemic immune dysregulation,immunosuppression,and potentially impaired bone healing.We found CD1d as a global marker for TIM cells in polytrauma.展开更多
Cirrhosis represents the end stage of chronic liver disease,significantly reducing life expectancy as it progresses from a compensated to a decompensated state,leading to serious complications.Recent improvements in m...Cirrhosis represents the end stage of chronic liver disease,significantly reducing life expectancy as it progresses from a compensated to a decompensated state,leading to serious complications.Recent improvements in medical treatment have created a shift in cirrhosis management.Various causes,including hepatitis viruses,alcohol consumption,and fatty liver disease,contribute to cirrhosis and are closely linked to liver cancer.The disease develops through hepatocyte necrosis and regeneration,resulting in fibrosis and sinusoidal capillarization,leading to portal hypertension and complications such as ascites,hepatic encephalopathy,and organ dysfunction.Cirrhosis also holds an increased risk of hepatocellular carcinoma.Diagnosing cirrhosis involves assessing fibrosis scores through blood tests and measuring liver stiffness through elastography.Liver transplantation is the definitive treatment for endstage liver disease and acute liver failure.展开更多
Chronic heart failure （CHF） is a highly prevalent condition among the elderly and is associated with considerable morbidity, institution-alization and mortality. In its advanced stages, CHF is often accompanied by t...Chronic heart failure （CHF） is a highly prevalent condition among the elderly and is associated with considerable morbidity, institution-alization and mortality. In its advanced stages, CHF is often accompanied by the loss of muscle mass and strength. Sarcopenia is a geriatric syndrome that has been actively studied in recent years due to its association with a wide range of adverse health outcomes. The goal of this review is to discuss the relationship between CHF and sarcopenia, with a focus on shared pathophysiological pathways and treatments. Mal- nutrition, systemic inflammation, endocrine imbalances, and oxidative stress appear to connect sarcopenia and CHF. At the muscular level, alterations of the ubiquitin proteasome system, myostatin signaling, and apoptosis have been described in both sarcopenia and CHF and could play a role in the loss of muscle mass and function. Possible therapeutic strategies to impede the progression of muscle wasting in CHF patients include protein and vitamin D supplementation, structured physical exercise, and the administration of angiotensin-converting enzyme inhibitors and β-blockers. Hormonal supplementation with growth hormone, testosterone, and ghrelin is also discussed as a potential treatment.展开更多
In regenerative medicine,extracellular vesicles(EVs)possess the potential to repair injured cells by delivering modulatory factors.However,the therapeutic effect of EVs in large-scale tissue defects,which are subject ...In regenerative medicine,extracellular vesicles(EVs)possess the potential to repair injured cells by delivering modulatory factors.However,the therapeutic effect of EVs in large-scale tissue defects,which are subject to prolonged timelines for tissue architecture and functional restoration,remains poorly understood.In this study,we introduce EVs and cell-tethering hybrid hydrogels composed of tyramine-conjugated gelatin(GelTA)that can be in-situ crosslinked with EVs derived from human induced pluripotent stem cell-derived myofibers(hiPSC-myofibers)and hiPSC-muscle precursor cells.This hybrid hydrogel sustains the release of EVs and provides a beneficial nano-topography and mechanical properties for creating a favorable extracellular matrix.Secreted EVs from the hiPSC-myofibers contain specific microRNAs,potentially improving myogenesis and angiogenesis.Herein,we demonstrate increased myogenic markers and fusion/differentiation indexes through the combina-tory effects of EVs and integrin-mediated adhesions in the 3D matrix.Furthermore,we observe a unique impact of EVs,which aid in maintaining the viability and phenotype of myofibers under harsh environments.The hybrid hydrogel in-situ crosslinked with hiPSCs and EVs is facilely used to fabricate large-scale muscle constructs by the stacking of micro-patterned hydrogel domains.Later,we confirmed a combinational effect,whereby muscle tissue regeneration and functional restoration were improved,via an in vivo murine volumetric muscle loss model.展开更多
Dear Editor Aging is linked to changes in brain function that lead to physical decline,including motor deficits and skeletal muscle loss.while maintaining motor activity is crucial for improving the quality of life in...Dear Editor Aging is linked to changes in brain function that lead to physical decline,including motor deficits and skeletal muscle loss.while maintaining motor activity is crucial for improving the quality of life in the elderly,there is limited research on strategies to prevent motor function decline and preserve skeletal muscle.Additionally.approaches to preserving the function of critical neural systems to mitigate age-related motor decline remain underexplored.展开更多
Craniofacial muscles are essential for a variety of functions,including fine facial expressions.Severe injuries to these muscles often lead to more devastating consequences than limb muscle injuries,resulting in the l...Craniofacial muscles are essential for a variety of functions,including fine facial expressions.Severe injuries to these muscles often lead to more devastating consequences than limb muscle injuries,resulting in the loss of critical functions such as mastication and eyelid closure,as well as facial aesthetic impairment.Therefore,the development of targeted repair strategies for craniofacial muscle injuries is crucial.In this study,we engineered an adipose-derived decellularized extracellular matrix(adECM)bioscaffold co-loaded with seed cells and bioactive factors.The seed cells were STIM1-overexpressing adipose-derived stem cells(STIM1-ASCs),which exhibit directed and highly efficient myogenic differentiation,addressing the low differentiation efficiency of conventional ASCs that limits muscle regeneration.The bioactive factor used was insulin-like growth factor-2(IGF-2),which modulates the immune microenvironment by reprogramming mitochondrial energy metabolism to promote M2 macrophage polarization.These M2 macrophages further suppress fibroblast collagen deposition,alleviating muscle fibrosis,while simultaneously enhancing the myogenic differentiation of STIM1-ASCs and myotube formation.Together,the recellularized adECM bioscaffold harnesses these dual mechanisms(promoting functional muscle regeneration and anti-fibrotic repair)to significantly improve the recovery of volumetric muscle loss(VML)in the masseter.The development of this bifunctional bioscaffold offers a novel therapeutic strategy and theoretical foundation for treating severe craniofacial muscle injuries.展开更多
基金supported by funding from the National Natural Science Foundation of China(82272478,82002330,82202728)the National Key R&D Program of China(No.2022YFF1100100)the Natural Science Foundation of Beijing(L222086).
文摘Systematic bone and muscle loss is a complex metabolic disease,which is frequently linked to gut dysfunction,yet its etiology and treatment remain elusive.While probiotics show promise in managing diseases through microbiome modulation,their therapeutic impact on gut dysfunction-induced bone and muscle loss remains to be elucidated.Employing dextran sulfate sodium(DSS)-induced gut dysfunction model and wide-spectrum antibiotics(ABX)-treated mice model,our study revealed that gut dysfunction instigates muscle and bone loss,accompanied by microbial imbalances.Importantly,Bifidobacterium animalis subsp.lactis A6(B.lactis A6)administration significantly ameliorated muscle and bone loss by modulating gut microbiota composition and enhancing butyrate-producing bacteria.This intervention effectively restored depleted butyrate levels in serum,muscle,and bone tissues caused by gut dysfunction.Furthermore,butyrate supplementation mitigated musculoskeletal loss by repairing the damaged intestinal barrier and enriching beneficial butyrate-producing bacteria.Importantly,butyrate inhibited the NF-κB pathway activation,and reduced the secretion of corresponding inflammatory factors in T cells.Our study highlights the critical role of dysbiosis in gut dysfunction-induced musculoskeletal loss and underscores the therapeutic potential of B.lactis A6.These discoveries offer new microbiome directions for translational and clinical research,providing promising strategies for preventing and managing musculoskeletal diseases.
基金supported by the National Research Foundation of Korea(NRF)grant funded by the Korean Government(the Ministry of Science and ICT(MSIT))(No.2021R1A2C2006013)the Bio&Medical Technology Development Program of the NRF funded by the Korean government(MSIT)(No.RS-2023-00223591)the Korea Medical Device Development Fund grant funded by the Korean government(the MSIT,the MOTIE,the Ministry of Health and Welfare,the Ministry of Food and Drug Safety)(NTIS Number:9991006781,KMDF_PR_(2)0200901_0108)。
文摘Current therapeutic approaches for volumetric muscle loss(VML)face challenges due to limited graft availability and insufficient bioactivities.To overcome these limitations,tissue-engineered scaffolds have emerged as a promising alternative.In this study,we developed aligned ternary nanofibrous matrices comprised of poly(lactide-co-ε-caprolactone)integrated with collagen and Ti_(3)C_(2)T_(x)MXene nanoparticles(NPs)(PCM matrices),and explored their myogenic potential for skeletal muscle tissue regeneration.The PCM matrices demonstrated favorable physicochemical properties,including structural uniformity,alignment,microporosity,and hydrophilicity.In vitro assays revealed that the PCM matrices promoted cellular behaviors and myogenic differentiation of C2C12 myoblasts.Moreover,in vivo experiments demonstrated enhanced muscle remodeling and recovery in mice treated with PCM matrices following VML injury.Mechanistic insights from next-generation sequencing revealed that MXene NPs facilitated protein and ion availability within PCM matrices,leading to elevated intracellular Ca^(2+)levels in myoblasts through the activation of inducible nitric oxide synthase(i NOS)and serum/glucocorticoid regulated kinase 1(SGK1),ultimately promoting myogenic differentiation via the m TOR-AKT pathway.Additionally,upregulated i NOS and increased NO–contributed to myoblast proliferation and fiber fusion,thereby facilitating overall myoblast maturation.These findings underscore the potential of MXene NPs loaded within highly aligned matrices as therapeutic agents to promote skeletal muscle tissue recovery.
基金This work was supported by a grant from The Plastic Surgery Foundation(PSF312406,to Q.Zhang)by the Kyte Fund through MD Anderson’s Department of Plastic Surgery+1 种基金This research was also supported by the NIH through MD Anderson’s Cancer Center Support Grant(P30CA016672)used MD Anderson’s High Resolution Electron Microscopy Facility,Flow Cytometry and Cellular Imaging Core Facility,and Proteomics and Metabolomics Core Facility.
文摘Muscle flaps must have a strong vascular network to support a large tissue volume and ensure successful engraftment.We developed porcine stomach musculofascial flap matrix(PDSF)comprising extracellular matrix(ECM)and intact vasculature.PDSF had a dominant vascular pedicle,microcirculatory vessels,a nerve network,well-retained 3-dimensional(3D)nanofibrous ECM structures,and no allo-or xenoantigenicity.In-depth proteomic analysis demonstrated that PDSF was composed of core matrisome proteins(e.g.,collagens,glycoproteins,proteoglycans,and ECM regulators)that,as shown by Gene Ontology term enrichment analysis,are functionally related to musculofascial biological processes.Moreover,PDSFhuman adipose-derived stem cell(hASC)synergy not only induced monocytes towards IL-10producing M2 macrophage polarization through the enhancement of hASCs’paracrine effect but also promoted the proliferation and interconnection of both human skeletal muscle myoblasts(HSMMs)and human umbilical vein endothelial cells(HUVECs)in static triculture conditions.Furthermore,PDSF was successfully prevascularized through a dynamic perfusion coculture of hASCs and HUVECs,which integrated with PDSF and induced the maturation of vascular networks in vitro.In a xenotransplantation model,PDSF demonstrated myoconductive and immunomodulatory properties associated with the predominance of M2 macrophages and regulatory T cells.In a volumetric muscle loss(VML)model,prevascularized PDSF augmented neovascularization and constructive remodeling,which was characterized by the predominant infiltration of M2 macrophages and significant musculofascial tissue formation.These results indicate that hASCs’integration with PDSF enhances the cells’dual function in immunomodulation and angiogenesis.Owing in part to this PDSF-hASC synergy,our platform shows promise for vascularized muscle flap engineering for VML reconstruction.
基金NIH R03AR068108,NIH R01AR071649 and Purdue Start-up Package is greatly appreciated.The authors acknowledge the use of Purdue Life Science Microscopy Facility,Purdue Histology Core Facility.The authors also acknowledge the use of facilities of the Bindley Bioscience Center,a core facility of the NIH-funded Indiana Clinical and Translational Sciences Institute.
文摘Volumetric muscle loss(VML)injuries characterized by critical loss of skeletal muscle tissues result in severe functional impairment.Current treatments involving use of muscle grafts are limited by tissue availability and donor site morbidity.In this study,we designed and synthesized an implantable glycosaminoglycan-based hydrogel system consisting of thiolated hyaluronic acid(HA)and thiolated chondroitin sulfate(CS)cross-linked with poly(ethylene glycol)diacrylate to promote skeletal muscle regeneration of VML injuries in mice.The HA-CS hydrogels were optimized with suitable biophysical properties by fine-tuning degree of thiol group substitution to support C2C12 myoblast proliferation,myogenic differentiation and expression of myogenic markers MyoD,MyoG and MYH8.Furthermore,in vivo studies using a murine quadriceps VML model demonstrated that the HA-CS hydrogels supported integration of implants with the surrounding host tissue and facilitated migration of Pax7+satellite cells,de novo myofiber formation,angiogenesis,and innervation with minimized scar tissue formation during 4-week implantation.The hydrogel-treated and autograft-treated mice showed similar functional improvements in treadmill performance as early as 1-week post-implantation compared to the untreated groups.Taken together,our results demonstrate the promise of HA-CS hydrogels as regenerative engineering matrices to accelerate healing of skeletal muscle injuries.
文摘Volumetric muscle loss(VML)refers to a composite,en bloc loss of skeletal muscle mass resulting in functional impairment.These injuries normally heal with excessive fibrosis,minimal skeletal muscle regeneration,and poor functional recovery.Functional muscle transfer is a treatment option for some patients but is limited both by the degree of functional restoration as well as donor site morbidity.As such,new therapeutic options are necessary.De novo regeneration of skeletal muscle,by way of tissue engineering,is an emerging strategy to treat VML.This review evaluates available scaffolds for promoting skeletal muscle regeneration and functional recovery following VML.The use of growth factors and stem cell therapies,which may augment scaffold integration and skeletal muscle reconstitution,are also discussed.Regenerative medicine with the use of scaffolds is a promising area in skeletal muscle reconstruction and VML treatment.
文摘Obesity affects over 1 billion people worldwide and is linked to more than 230 health complications,with cardiovascular disease being a leading cause of mortality.Losing 5%-10%of body weight is considered clinically significant for improving health.This weight loss can be achieved through pharmacotherapy,including glucagon-like peptide 1(GLP-1)receptor agonists,GLP-1/glucosedependent insulinotropic peptide dual receptor agonists,and GLP-1/glucosedependent insulinotropic peptide/glucagon triple receptor agonists(such as semaglutide,tirzepatide,and retatrutide,respectively).While much of the weight loss comes from fat mass,these treatments also result in the loss of lean mass,including muscle.This loss of muscle may contribute to difficulties in maintaining weight over the long term and can lead to sarcopenia.Therefore,the focus of new anti-obesity treatments should be primarily on reducing fat mass while minimizing the loss of muscle mass,ideally promoting muscle gain.Research focusing on human myocytes has identified more than 600 myokines associated with muscle contraction,which may play a crucial role in preserving both muscle mass and function.We explored the potential of new anti-obesity agents and their combinations with incretin-based therapies to achieve these outcomes.Further studies are needed to better understand the functional implications of lean mass expansion during weight loss and weight maintenance programs.
基金supported by the National Natural Science Foundation of China(32372925)the Science and Technology Innovation Program of Hunan Province(2022RC1159)+2 种基金the Changsha Natural Science Funds for Distinguished Young Scholar(kq2009020)the National Key Research and Development Programs of China(2022YFD1300503)the China Agriculture Research System of MOF and MARA(CARS35)。
文摘We previously demonstrated that lipopolysaccharide(LPS)injection-induced immune stress could impair muscle growth in weaned piglets,but the precise mechanisms behind this remain elusive.Here,we found that chronic immune stress induced by LPS resulted in a significant reduction of 36.86%in the total muscle mass of piglets at 5 d post-treatment compared with the control group.At 1 d,prior to muscle mass loss,multiple alterations were noted in response to LPS treatment.These included a reduction in the abundance of Bacteroidetes,an increase in serum concentrations of pro-inflammatory cytokines,compromised mitochondrial morphology,and an upregulation in the expression of dynamin-related protein 1(Drp1),a critical protein involved in mitochondrial fission.We highlight a strong negative correlation between Bacteroidetes abundance and the levels of serum pro-inflammatory cytokines,corroborated by in vivo intervention strategies in the musculature of both pig and mouse models.Mechanistically,the effects of Bacteroidetes on inflammation and muscle mass loss may involve the signaling pathway of the tauro-β-muricholic acid-fibroblast growth factor 15.Furthermore,the induction of overexpression of inflammatory cytokines,achieved without LPS treatment through oral administration of recombinant human IL-6(rh IL-6),led to increased levels of circulating cytokines,subsequently causing a decrease in muscle mass.Notably,pre-treatment with Mdivi-1,an inhibitor of Drp-1,markedly attenuated the LPS-induced elevation in reactive oxygen species levels and rescued the associated decline in muscle mass.Collectively,these data indicate that LPS-induced muscle mass loss was linked to the reduction of Bacteroidetes abundance,increased inflammation,and the disruption of mitochondrial morphology.These insights offer promising avenues for the identification of potential therapeutic targets aimed at mitigating muscle mass loss.
基金supported by the National Science Foundation(CBET 1751554)the National Institutes of Health,the Arkansas Integrative Metabolic Research Center(5P20GM139768-02)the Arkansas Biosciences Institute.Any opinions,-ndings,and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of the acknowledged funding agencies.
文摘Nicotinamide adenine dinucleotide(NADH)is a cofactor that serves to shuttle electrons during metabolic processes such as glycolysis,the tricarboxylic acid cycle,and oxidative phosphorylation(OXPHOS).NADH is autofluorescent,and itsfluorescence lifetime can be used to infer metabolic dynamics in living cells.Fiber-coupled time-correlated single photon counting(TCSPC)equipped with an implantable needle probe can be used to measure NADH lifetime in vivo,enabling investigation of changing metabolic demand during muscle contraction or tissue regeneration.This study illustrates a proof of concept for point-based,minimally-invasive NADHfluorescence lifetime measurement in vivo.Volumetric muscle loss(VML)injuries were created in the left tibialis anterior(TA)muscle of male Sprague Dawley rats.NADH lifetime measurements were collected before,during,and after a 30 s tetanic contraction in the injured and uninjured TA muscles,which was subsequently-t to a biexponential decay model to yield a metric of NADH utilization(cytoplasmic vs protein-bound NADH,the A11/A22 ratio).On average,this ratio was higher during and after contraction in uninjured muscle compared to muscle at rest,suggesting higher levels of free NADH in contracting and recovering muscle,indicating increased rates of glycolysis.In injured muscle,this ratio was higher than uninjured muscle overall but decreased over time,which is consistent with current knowledge of inflammatory response to injury,suggesting tissue regeneration has occurred.These data suggest that-ber-coupled TCSPC has the potential to measure changes in NADH binding in vivo in a minimally invasive manner that requires further investigation.
基金supported in part by the National Natural Science Foundation of China(Grant No.82350710800,82374470,82202757)Shenzhen Medical Research Fund B2302005,and NHMRC,APP1163933.
文摘Rheumatoid arthritis(RA)is a prevalent and debilitating inflammatory disease that significantly impairs functional capacity and quality of life.RA accelerates musculoskeletal aging,leading to complications such as muscle degeneration and sarcopenia.Recent research has identified myopenia as a condition of significant muscle loss associated with illness,distinct from the muscle wasting seen in other chronic diseases like cancer cachexia or heart failure.In RA,myopenia is characterized by muscle depletion without concurrent significant fat loss,and it can affect individuals of all ages.While inflammation plays a central role,it is not the sole factor contributing to the high incidence of muscle wasting in RA.In subsequent discussions,secondary sarcopenia will be considered alongside myopenia,as both involve muscle wasting decline primarily due to disease.This review summarizes recent findings on the impact of RA-related myopenia and secondary sarcopenia on functional capacity,explores its underlying mechanisms,and discusses contemporary strategies to mitigate the process of musculoskeletal aging in RA patients.
文摘Polytrauma with significant bone and volumetric muscle loss presents substantial clinical challenges.Although immune responses significantly influence fracture healing post-polytrauma,the cellular and molecular underpinnings of polytrauma-induced immune dysregulation require further investigation.While previous studies examined either injury site tissue or systemic tissue(peripheral blood),our study uniquely investigated both systemic and local immune cells at the same time to better understand polytrauma-induced immune dysregulation and associated impaired bone healing.Using single-cell RNA sequencing(scRNA-seq)in a rat polytrauma model,we analyzed blood,bone marrow,and the local defect soft tissue to identify potential cellular and molecular targets involved in immune dysregulation.We identified a trauma-associated immunosuppressive myeloid(TIM)cell population that drives systemic immune dysregulation,immunosuppression,and potentially impaired bone healing.We found CD1d as a global marker for TIM cells in polytrauma.
文摘Cirrhosis represents the end stage of chronic liver disease,significantly reducing life expectancy as it progresses from a compensated to a decompensated state,leading to serious complications.Recent improvements in medical treatment have created a shift in cirrhosis management.Various causes,including hepatitis viruses,alcohol consumption,and fatty liver disease,contribute to cirrhosis and are closely linked to liver cancer.The disease develops through hepatocyte necrosis and regeneration,resulting in fibrosis and sinusoidal capillarization,leading to portal hypertension and complications such as ascites,hepatic encephalopathy,and organ dysfunction.Cirrhosis also holds an increased risk of hepatocellular carcinoma.Diagnosing cirrhosis involves assessing fibrosis scores through blood tests and measuring liver stiffness through elastography.Liver transplantation is the definitive treatment for endstage liver disease and acute liver failure.
文摘Chronic heart failure （CHF） is a highly prevalent condition among the elderly and is associated with considerable morbidity, institution-alization and mortality. In its advanced stages, CHF is often accompanied by the loss of muscle mass and strength. Sarcopenia is a geriatric syndrome that has been actively studied in recent years due to its association with a wide range of adverse health outcomes. The goal of this review is to discuss the relationship between CHF and sarcopenia, with a focus on shared pathophysiological pathways and treatments. Mal- nutrition, systemic inflammation, endocrine imbalances, and oxidative stress appear to connect sarcopenia and CHF. At the muscular level, alterations of the ubiquitin proteasome system, myostatin signaling, and apoptosis have been described in both sarcopenia and CHF and could play a role in the loss of muscle mass and function. Possible therapeutic strategies to impede the progression of muscle wasting in CHF patients include protein and vitamin D supplementation, structured physical exercise, and the administration of angiotensin-converting enzyme inhibitors and β-blockers. Hormonal supplementation with growth hormone, testosterone, and ghrelin is also discussed as a potential treatment.
基金funded by the National Institutes of Health(R01AR077132)AHA collaborative award(944227)+3 种基金the Gillian Reny Stepping Strong Center for Trauma Innovationpartially supported by Basic Science Research Program through the National Research Foundation of Korea(NRF)funded by the Ministry of Education(NRF-2021R1A6A3A14039720)supporting Jiseong Kim and Jieun Jeon by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI),funded by the Minstry of Health&Welfare,Republic of Korea(HI19C0757)partially funded by the Deanship of Scientific Research(DSR)at King Abdulaziz University,Jeddah,under Grant No.RG-22-135-39.
文摘In regenerative medicine,extracellular vesicles(EVs)possess the potential to repair injured cells by delivering modulatory factors.However,the therapeutic effect of EVs in large-scale tissue defects,which are subject to prolonged timelines for tissue architecture and functional restoration,remains poorly understood.In this study,we introduce EVs and cell-tethering hybrid hydrogels composed of tyramine-conjugated gelatin(GelTA)that can be in-situ crosslinked with EVs derived from human induced pluripotent stem cell-derived myofibers(hiPSC-myofibers)and hiPSC-muscle precursor cells.This hybrid hydrogel sustains the release of EVs and provides a beneficial nano-topography and mechanical properties for creating a favorable extracellular matrix.Secreted EVs from the hiPSC-myofibers contain specific microRNAs,potentially improving myogenesis and angiogenesis.Herein,we demonstrate increased myogenic markers and fusion/differentiation indexes through the combina-tory effects of EVs and integrin-mediated adhesions in the 3D matrix.Furthermore,we observe a unique impact of EVs,which aid in maintaining the viability and phenotype of myofibers under harsh environments.The hybrid hydrogel in-situ crosslinked with hiPSCs and EVs is facilely used to fabricate large-scale muscle constructs by the stacking of micro-patterned hydrogel domains.Later,we confirmed a combinational effect,whereby muscle tissue regeneration and functional restoration were improved,via an in vivo murine volumetric muscle loss model.
基金supported by grants from the National Research Foundation of Korea(MSIT:RS-2024-00408736,NRF-2020R1A2C2007954,and2017R1A2B4002675)funded by the Korean government.
文摘Dear Editor Aging is linked to changes in brain function that lead to physical decline,including motor deficits and skeletal muscle loss.while maintaining motor activity is crucial for improving the quality of life in the elderly,there is limited research on strategies to prevent motor function decline and preserve skeletal muscle.Additionally.approaches to preserving the function of critical neural systems to mitigate age-related motor decline remain underexplored.
基金National Natural Science Foundation of China(NO.82503035)Beijing Natural Science Foundation(NO.7254442)+3 种基金China Postdoctoral Science Foundation(NO.2024M750129)Postdoctoral Fellowship Program of CPSF(NO.GZC20230151)Peking University Medicine Sailing Program for Young Scholars’Scientific&Technological Inno-vation(NO.BMU2024YFJHPY030)Peking University Third Hospital Fund for Interdisciplinary Research(NO.BMU2025XY032).
文摘Craniofacial muscles are essential for a variety of functions,including fine facial expressions.Severe injuries to these muscles often lead to more devastating consequences than limb muscle injuries,resulting in the loss of critical functions such as mastication and eyelid closure,as well as facial aesthetic impairment.Therefore,the development of targeted repair strategies for craniofacial muscle injuries is crucial.In this study,we engineered an adipose-derived decellularized extracellular matrix(adECM)bioscaffold co-loaded with seed cells and bioactive factors.The seed cells were STIM1-overexpressing adipose-derived stem cells(STIM1-ASCs),which exhibit directed and highly efficient myogenic differentiation,addressing the low differentiation efficiency of conventional ASCs that limits muscle regeneration.The bioactive factor used was insulin-like growth factor-2(IGF-2),which modulates the immune microenvironment by reprogramming mitochondrial energy metabolism to promote M2 macrophage polarization.These M2 macrophages further suppress fibroblast collagen deposition,alleviating muscle fibrosis,while simultaneously enhancing the myogenic differentiation of STIM1-ASCs and myotube formation.Together,the recellularized adECM bioscaffold harnesses these dual mechanisms(promoting functional muscle regeneration and anti-fibrotic repair)to significantly improve the recovery of volumetric muscle loss(VML)in the masseter.The development of this bifunctional bioscaffold offers a novel therapeutic strategy and theoretical foundation for treating severe craniofacial muscle injuries.
