Abstract
Skeletal muscle is a regenerative tissue which can repair damaged myofibers through the activation of tissue-resident muscle stem cells (MuSCs). Many muscle diseases with impaired regeneration cause excessive adipose tissue accumulation in muscle, alter the myogenic fate of MuSCs, and deregulate the cross-talk between MuSCs and fibro/adipogenic progenitors (FAPs), a bi-potent cell population which supports myogenesis and controls intra-muscular fibrosis and adipocyte formation. In order to better characterize the interaction between adipogenesis and myogenesis, we studied muscle regeneration and MuSC function in whole body Pparg null mice generated by epiblast-specific Cre/lox deletion (PpargΔ/Δ). We demonstrate that deletion of PPARγ completely abolishes ectopic muscle adipogenesis during regeneration and impairs MuSC expansion and myogenesis after injury. Ex vivo assays revealed that perturbed myogenesis in PpargΔ/Δ mice does not primarily result from intrinsic defects of MuSCs or from perturbed myogenic support from FAPs. The immune transition from a pro- to anti-inflammatory MuSC niche during regeneration is perturbed in PpargΔ/Δ mice and suggests that PPARγ signaling in macrophages can interact with ectopic adipogenesis and influence muscle regeneration. Altogether, our study demonstrates that a PPARγ-dependent adipogenic response regulates muscle fat infiltration during regeneration and that PPARγ is required for MuSC function and efficient muscle repair.
Highlights
Skeletal muscle is a highly plastic tissue, which can adapt to different metabolic or physical challenges, such as physical activity, disuse, or injuries
By analyzing histological and molecular readouts in vivo and the cross-talk between fibro/adipogenic progenitors (FAPs) and muscle stem cells (MuSCs) in vitro, we demonstrate that the loss of peroxisome proliferator-activated receptor γ (PPARγ) totally blunts ectopic adipogenesis during muscle regeneration and alters MuSC function and regeneration
Several studies have reported an upregulation of PPARγ during skeletal muscle regeneration, which precedes the infiltration of lipid-droplet positive cells [24,26]
Summary
Skeletal muscle is a highly plastic tissue, which can adapt to different metabolic or physical challenges, such as physical activity, disuse, or injuries. When muscle fibers are damaged as a consequence of intense exercise, trauma, surgery, or genetic diseases, complementary cellular mechanisms allow skeletal muscle to regenerate and recover tissue architecture and functionality This regenerative capacity is primarily driven by muscle stem cells (MuSCs), known as satellite cells, which express the transcription factor paired box 7 (Pax7) [1,2]. We and others have shown that various models of muscle injury induced by intra-muscular injection of cardiotoxin (CTX) or glycerol lead to ectopic adipogenesis in muscle with accumulation of fat containing cells between muscle fibers [24,25,26,27] Under physiological conditions, this response is transient and cleared during the terminal phases of regeneration. By analyzing histological and molecular readouts in vivo and the cross-talk between FAPs and MuSCs in vitro, we demonstrate that the loss of PPARγ totally blunts ectopic adipogenesis during muscle regeneration and alters MuSC function and regeneration
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
