Myostatin(MSTN)is principally expressed in skeletal muscle and negatively regulates muscle growth and development.MSTN mutation can induce muscle overgrowth in cattle by activating cell proliferation,presenting a“dou...Myostatin(MSTN)is principally expressed in skeletal muscle and negatively regulates muscle growth and development.MSTN mutation can induce muscle overgrowth in cattle by activating cell proliferation,presenting a“double-muscle”phenotype.However,the specific regulatory mechanism is still unclear.Here,we found that Ca^(2+)content in muscle tissue and muscle satellite cells of MSTN mutated(MSTN^(–/–))cattle were significantly increased compared to wild-type(WT).Furthermore,transcriptome analysis of muscle satellite cells revealed that TRPC4 was significantly increased in MSTN^(–/–)cattle.And the expression of TRPC4 in muscle tissue of MSTN^(–/–)cattle was detected by RT-qPCR and Western blot,which was significantly higher than that of WT.These results suggested that MSTN mutation promoted muscle satellite cells proliferation through activation of TRPC4 channel.To further verify,ML204,a specific inhibitor of TRPC4,was used to treat MSTN^(–/–)muscle satellite cells.We found that cell proliferation was inhibited,calcineurin expression was downregulated,and the entry of NFATc3 into nuclei was reduced,which was similar to WT group.Thus,MSTN mutation leads to the activation of TRPC4 channel,which increases intracellular Ca^(2+)content,further activates calcineurin/NFATc3 pathway,and ultimately promotes the proliferation of muscle satellite cells.展开更多
Canonical transient receptor potential 4(TRPC4) forms non-selective cation channels that contribute to phospholipase C-dependent Ca2+ entry into cells following stimulation of G protein coupled receptors and receptor ...Canonical transient receptor potential 4(TRPC4) forms non-selective cation channels that contribute to phospholipase C-dependent Ca2+ entry into cells following stimulation of G protein coupled receptors and receptor tyrosine kinases.Moreover,the channels are regulated by pertussis toxin-sensitive Gi/o proteins,lipids,and various other signaling mechanisms.TRPC4-containing channels participate in the regulation of a variety of physiological functions,including excitability of both gastrointestinal smooth muscles and brain neurons.This review is to present recent advances in the understanding of physiology and development of small molecular modulators of TRPC4 channels.展开更多
基金supported by the National Natural Science Foundation of China(32360837 and 32341052)the STI2030 Major Projects,China(2023ZW0404803)+8 种基金the Inner Mongolia Open Competition Projects,China(2022JBGS0025)the Inner Mongolia Science and Technology Leading Team,China(2022LJRC0006)the Inner Mongolia Science and Technology Major Projects,China(2021ZD0009,2021ZD0008,2022ZD0008,2023KJHZ0028)the Inner Mongolia Young Talents Projects,China(NJYT23138)the Inner Mongolia Natural Science Foundation,China(2023MS03004)the Central Government Guides Development,China(2022ZY0212)the National Agricultural Science and Technology Project of China(NK2022130203)the Collaborative Innovation among Universities in Hohhot,China(XTCX2023-06)the Ministry of Education Engineering Centre Project,China(JYBGCSYS2022)。
文摘Myostatin(MSTN)is principally expressed in skeletal muscle and negatively regulates muscle growth and development.MSTN mutation can induce muscle overgrowth in cattle by activating cell proliferation,presenting a“double-muscle”phenotype.However,the specific regulatory mechanism is still unclear.Here,we found that Ca^(2+)content in muscle tissue and muscle satellite cells of MSTN mutated(MSTN^(–/–))cattle were significantly increased compared to wild-type(WT).Furthermore,transcriptome analysis of muscle satellite cells revealed that TRPC4 was significantly increased in MSTN^(–/–)cattle.And the expression of TRPC4 in muscle tissue of MSTN^(–/–)cattle was detected by RT-qPCR and Western blot,which was significantly higher than that of WT.These results suggested that MSTN mutation promoted muscle satellite cells proliferation through activation of TRPC4 channel.To further verify,ML204,a specific inhibitor of TRPC4,was used to treat MSTN^(–/–)muscle satellite cells.We found that cell proliferation was inhibited,calcineurin expression was downregulated,and the entry of NFATc3 into nuclei was reduced,which was similar to WT group.Thus,MSTN mutation leads to the activation of TRPC4 channel,which increases intracellular Ca^(2+)content,further activates calcineurin/NFATc3 pathway,and ultimately promotes the proliferation of muscle satellite cells.
基金This work was supported by the National Basic Research Priorities Programme of China (G 1999054007) and Foundation of Ministry of Education of China (No.200066).
基金supported in part by the National Natural Science Foundation of China(81228021)US National Institutes of Health(DK081654)
文摘Canonical transient receptor potential 4(TRPC4) forms non-selective cation channels that contribute to phospholipase C-dependent Ca2+ entry into cells following stimulation of G protein coupled receptors and receptor tyrosine kinases.Moreover,the channels are regulated by pertussis toxin-sensitive Gi/o proteins,lipids,and various other signaling mechanisms.TRPC4-containing channels participate in the regulation of a variety of physiological functions,including excitability of both gastrointestinal smooth muscles and brain neurons.This review is to present recent advances in the understanding of physiology and development of small molecular modulators of TRPC4 channels.
