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.

CD8 T Cells Are Involved in Skeletal Muscle Regeneration through Facilitating MCP-1 Secretion and Gr1high Macrophage Infiltration

“…The muscle regeneration model was performed as described previously (22). In brief, after anesthesia with pentobarbital sodium, tibialis anterior (TA) muscles were injected with 10 mM CTX (Sigma-Aldrich, St. Louis, MO) in saline (40 ml), whereas the group of Sham muscles was injected with saline.…”

Low-Frequency Electrical Stimulation Attenuates Muscle Atrophy in CKD—A Potential Treatment Strategy

“…In general, upregulation of insulin and IGF-1 signaling will prevent against muscle atrophy induced by CKD. 5,8,[18][19][20] IGF-1 is predominantly made by the liver. Recent studies strongly implicate macrophages as the major extrahepatic source of IGF-1 that contributes to the control of postnatal growth and organ maturation.…”

Progressive Resistance Exercise Training Attenuated Renal Damages, but did not improve Muscle Force in STZ-Induced Diabetic Rats

“…Catabolic condition-induced skeletal muscle atrophy, such as diabetes and CKD, normally lead skeletal muscle to loss of muscle weight and function, and this is at least in part due to increased inflammation and insulin resistance [10,[20][21][22][23]. As we known, activation of muscle fibers by resistance exercise training (RET) or injury may increase mTORC1 activation improving protein synthesis and regulating several cellular process including translation and transcription [2,10,24].…”

“…Protein breakdown may be increased through the activation of the ubiquitin-proteasome system that is markedly involved in muscle atrophy increasing mRNA and proteins known as atrogenes such as, MuRF1 and Atrogin-1 [25][26][27]. On the other hand, catabolic conditions may decrease skeletal muscle hypertrophy with no involvement of atrogenes, by decreasing activation of mTOR and its downstream, such as p70 S6K and 4EBP1 [10,21,[28][29][30][31]. PI3K/Akt/mTOR-signaling pathway has been positively and extensively implicated on skeletal muscle hypertrophy under pathologic conditions.…”