title: Satellite cell dysfunction and impaired IGF-1 signaling cause CKD-induced muscle atrophy.
abstract: Muscle wasting in chronic kidney disease (CKD) begins with impaired insulin/IGF-1 signaling, causing abnormal protein metabolism. In certain models of muscle atrophy, reduced satellite cell function contributes to atrophy, but how CKD affects satellite cell function is unknown. Here, we found that isolated satellite cells from mice with CKD had less MyoD, the master switch of satellite cell activation, and suppressed myotube formation compared with control mice. In vivo, CKD delayed the regeneration of injured muscle and decreased MyoD and myogenin expression, suggesting that CKD impairs proliferation and differentiation of satellite cells. In isolated satellite cells from control mice, IGF-1 increased the expression of myogenic genes through an Akt-dependent pathway. CKD impaired Akt phosphorylation in satellite cells after muscle injury. To test whether impaired IGF-1 signaling could be responsible for decreased satellite cell function in CKD, we created an inducible IGF-1 receptor knockout mouse and found impaired satellite cell function and muscle regeneration. In addition, both CKD and IGF-1 receptor knockout mice developed fibrosis in regenerating muscles. Taken together, impaired IGF-1 signaling in CKD not only leads to abnormal protein metabolism in muscle but also impairs satellite cell function and promotes fibrosis in regenerating muscle. These signaling pathways may hold potential therapeutic targets to reduce CKD-related muscle wasting.
authors.affiliation: Nephrology Division, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Zhang
authors.forename: Xiaonan H
authors.initials: XH
authors.lastname: Wang
authors.forename: Huiling
authors.initials: H
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.forename: William E
authors.initials: WE
authors.lastname: Mitch
mesh_terms: D000818:Animals; D005355:Fibrosis; D015870:Gene Expression / Q000502:physiology; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D017570:MyoD Protein / Q000235:genetics; D009210:Myofibrils / Q000378:metabolism / Q000473:pathology; D051787:Myogenic Regulatory Factor 5 / Q000235:genetics; D018008:Myogenin / Q000235:genetics; D009220:Myositis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D012038:Regeneration / Q000502:physiology; D051436:Renal Insufficiency, Chronic / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D007328:Insulin; C497418:Myf5 protein, mouse; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; C503801:Myog protein, mouse; D051787:Myogenic Regulatory Factor 5; D018008:Myogenin; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I