Skeletal muscles are essential for locomotion,posture,and metabolic regulation.To understand physiological processes,exercise adaptation,and muscle-related disorders,it is critical to understand the molecular pathways...Skeletal muscles are essential for locomotion,posture,and metabolic regulation.To understand physiological processes,exercise adaptation,and muscle-related disorders,it is critical to understand the molecular pathways that underlie skeletal muscle function.The process of muscle contra ction,orchestrated by a complex interplay of molecular events,is at the core of skeletal muscle function.Muscle contraction is initiated by an action potential and neuromuscular transmission requiring a neuromuscular junction.Within muscle fibers,calcium ions play a critical role in mediating the interaction between actin and myosin filaments that generate force.Regulation of calcium release from the sarcoplasmic reticulum plays a key role in excitation-contraction coupling.The development and growth of skeletal muscle are regulated by a network of molecular pathways collectively known as myogenesis.Myogenic regulators coordinate the diffe rentiation of myoblasts into mature muscle fibers.Signaling pathways regulate muscle protein synthesis and hypertrophy in response to mechanical stimuli and nutrient availability.Seve ral muscle-related diseases,including congenital myasthenic disorders,sarcopenia,muscular dystrophies,and metabolic myopathies,are underpinned by dys regulated molecular pathways in skeletal muscle.Therapeutic interventions aimed at preserving muscle mass and function,enhancing regeneration,and improving metabolic health hold promise by targeting specific molecular pathways.Other molecular signaling pathways in skeletal muscle include the canonical Wnt signaling pathway,a critical regulator of myogenesis,muscle regeneration,and metabolic function,and the Hippo signaling pathway.In recent years,more details have been uncovered about the role of these two pathways during myogenesis and in developing and adult skeletal muscle fibers,and at the neuromuscular junction.In fact,research in the last few years now suggests that these two signaling pathways are interconnected and that they jointly control physiological and pathophysiological processes in muscle fibers.In this review,we will summarize and discuss the data on these two pathways,focusing on their concerted action next to their contribution to skeletal muscle biology.However,an in-depth discussion of the noncanonical Wnt pathway,the fibro/a dipogenic precursors,or the mechanosensory aspects of these pathways is not the focus of this review.展开更多
Ferroptosis is a novel form of iron-dependent cell death characterized by lipid per-oxidation.While the importance and disease relevance of ferroptosis is gaining recognition,much remains unknown about various genetic...Ferroptosis is a novel form of iron-dependent cell death characterized by lipid per-oxidation.While the importance and disease relevance of ferroptosis is gaining recognition,much remains unknown about various genetic and non-genetic determinants of ferroptosis.Hippo signaling pathway is an evolutionarily conserved pathway that responds to various envi-ronmental cues and controls organ size,cell proliferation,death,and self-renewal capacity.In cancer biology,Hippo pathway is a potent tumor suppressing mechanism and its dysregulation contributes to apoptosis evasion,cancer development,metastasis,and treatment resistance.Hippo dysregulation leads to aberrant activation of YAP and TAZ,the two major transcription co-activators of TEADs,that induce the expression of genes triggering tumor-promoting pheno-types,including enhanced cell proliferation,self-renewal and apoptosis inhibition.The Hippo pathway is regulated by the cell-cell contact and cellular density/confluence.Recently,fer-roptosis has also been found being regulated by the cellular contact and density.The YAP/TAZ activation under low density,while confers apoptosis resistance,renders cancer cells sensitivity to ferroptosis.These findings establish YAP/TAZ and Hippo pathways as novel deter-minants of ferroptosis.Therefore,inducing ferroptosis may have therapeutic potential for YAP/TAZ-activated chemo-resistant and metastatic tumor cells.Reciprocally,various YAP/TAZ-targeting treatments under clinical development may confer ferroptosis resistance,limiting the therapeutic efficacy.展开更多
基金supported by the German Research Council(Deutsche Forschungsgemeinschaft,HA3309/3-1/2,HA3309/6-1,HA3309/7-1)。
文摘Skeletal muscles are essential for locomotion,posture,and metabolic regulation.To understand physiological processes,exercise adaptation,and muscle-related disorders,it is critical to understand the molecular pathways that underlie skeletal muscle function.The process of muscle contra ction,orchestrated by a complex interplay of molecular events,is at the core of skeletal muscle function.Muscle contraction is initiated by an action potential and neuromuscular transmission requiring a neuromuscular junction.Within muscle fibers,calcium ions play a critical role in mediating the interaction between actin and myosin filaments that generate force.Regulation of calcium release from the sarcoplasmic reticulum plays a key role in excitation-contraction coupling.The development and growth of skeletal muscle are regulated by a network of molecular pathways collectively known as myogenesis.Myogenic regulators coordinate the diffe rentiation of myoblasts into mature muscle fibers.Signaling pathways regulate muscle protein synthesis and hypertrophy in response to mechanical stimuli and nutrient availability.Seve ral muscle-related diseases,including congenital myasthenic disorders,sarcopenia,muscular dystrophies,and metabolic myopathies,are underpinned by dys regulated molecular pathways in skeletal muscle.Therapeutic interventions aimed at preserving muscle mass and function,enhancing regeneration,and improving metabolic health hold promise by targeting specific molecular pathways.Other molecular signaling pathways in skeletal muscle include the canonical Wnt signaling pathway,a critical regulator of myogenesis,muscle regeneration,and metabolic function,and the Hippo signaling pathway.In recent years,more details have been uncovered about the role of these two pathways during myogenesis and in developing and adult skeletal muscle fibers,and at the neuromuscular junction.In fact,research in the last few years now suggests that these two signaling pathways are interconnected and that they jointly control physiological and pathophysiological processes in muscle fibers.In this review,we will summarize and discuss the data on these two pathways,focusing on their concerted action next to their contribution to skeletal muscle biology.However,an in-depth discussion of the noncanonical Wnt pathway,the fibro/a dipogenic precursors,or the mechanosensory aspects of these pathways is not the focus of this review.
基金support from the members of the Chilab.We acknowledge the financial support in part by DOD(grant numbers W81XWH-17-1-0143,W81XWH-15-1-0486,W81XWH-19-1-0842)NIH(grant numbers GM124062,1R01NS111588-01A1).
文摘Ferroptosis is a novel form of iron-dependent cell death characterized by lipid per-oxidation.While the importance and disease relevance of ferroptosis is gaining recognition,much remains unknown about various genetic and non-genetic determinants of ferroptosis.Hippo signaling pathway is an evolutionarily conserved pathway that responds to various envi-ronmental cues and controls organ size,cell proliferation,death,and self-renewal capacity.In cancer biology,Hippo pathway is a potent tumor suppressing mechanism and its dysregulation contributes to apoptosis evasion,cancer development,metastasis,and treatment resistance.Hippo dysregulation leads to aberrant activation of YAP and TAZ,the two major transcription co-activators of TEADs,that induce the expression of genes triggering tumor-promoting pheno-types,including enhanced cell proliferation,self-renewal and apoptosis inhibition.The Hippo pathway is regulated by the cell-cell contact and cellular density/confluence.Recently,fer-roptosis has also been found being regulated by the cellular contact and density.The YAP/TAZ activation under low density,while confers apoptosis resistance,renders cancer cells sensitivity to ferroptosis.These findings establish YAP/TAZ and Hippo pathways as novel deter-minants of ferroptosis.Therefore,inducing ferroptosis may have therapeutic potential for YAP/TAZ-activated chemo-resistant and metastatic tumor cells.Reciprocally,various YAP/TAZ-targeting treatments under clinical development may confer ferroptosis resistance,limiting the therapeutic efficacy.
