Satellite cell self‐renewal in endurance exercise is mediated by inhibition of mitochondrial oxygen consumption

Abstract

Background Skeletal muscle stem cells (satellite cells) are well known to participate in regeneration and maintenance of the tissue over time. Studies have shown increases in the number of satellite cells after exercise, but their functional role in endurance training remains unexplored. Methods Young adult mice were submitted to endurance exercise training and the function, differentiation, and metabolic characteristics of satellite cells were investigated in vivo and in vitro. Results We found that injured muscles from endurance-exercised mice display improved regenerative capacity, demonstrated through higher densities of newly formed myofibres compared with controls (evidenced by an increase in embryonic myosin heavy chain expression), as well as lower inflammation (evidenced by quantifying CD68-marked macrophages), and reduced fibrosis. Enhanced myogenic function was accompanied by an increased fraction of satellite cells expressing self-renewal markers, while control satellite cells had morphologies suggestive of early differentiation. The beneficial effects of endurance exercise were associated with satellite cell metabolic reprogramming, including reduced mitochondrial respiration (O 2 consumption) under resting conditions (absence of muscle injury) and increased stemness. During proliferation or activated states (3 days after injury), O 2 consumption was equal in control and exercised cells, while exercise enhanced myogenic colony formation. Surprisingly, inhibition of mitochondrial O 2 consumption was sufficient to enhance muscle stem cell self-renewal characteristics in vitro. Moreover, transplanted muscle satellite cells from exercised mice or cells with reduced mitochondrial respiration promoted a significant reduction in inflammation compared with controls. Conclusions Our results indicate that endurance exercise promotes self-renewal and inhibits differentiation in satellite cells, an effect promoted by metabolic reprogramming and respiratory inhibition, which is associated with a more favourable muscular response to injury.

Superiority of focused ion beam‐scanning electron microscope tomography of cardiomyocytes over standard 2D analyses highlighted by unmasking mitochondrial heterogeneity

“…Based on the protein quantification, the mitochondrial suspensions, isolated mitochondria from WT ( n = 5) and Bnip3 −/− mice ( n = 5) were diluted to the working concentration of 4 μg/mL total protein with cold 1× mitochondrial assay solution (MAS) (2 mM HEPES, 10 mM KH 2 PO 4 , 220 mM mannitol, 1 mM EGTA, 70 mM sucrose, 5 mM MgCl 2 , 0.2% fatty acid‐free bovine albumin serum (BSA), pH 7.2) supplemented with 10 mM succinate and 2 μM rotenone. The wells of an XF24 V7 PS 24‐well cell culture microplate 34 (Agilent Technologies, Santa Clara, CA, USA) were loaded with five replicates of 50 μL of diluted mitochondria suspension (2 μg protein/well). For background correction, the corners were filled with only 1 × MAS.…”

Vitamin D Promotes Skeletal Muscle Regeneration and Mitochondrial Health

“…Quiescent SCs have less mitochondria and lower oxidative capacity than activated, differentiating SCs, and mitochondrial activity is a key process underlying SC activation (Latil et al, 2012). This lower oxidative capacity has been recapitulated in vivo, where reduced mitochondrial respiration of SCs was associated with a greater proportion of SCs expressing self-renewal markers in endurance-trained mice (Abreu and Kowaltowski, 2020). In addition to the importance of metabolic reprogramming, other mitochondrial processes are implicated in optimal SC function.…”

Pathophysiology and Treatment Strategies of Acute Myopathy and Muscle Wasting after Sepsis

“…The loss of mitochondrial metabolic homeostasis is also a likely contributor to SC dysfunctions and stability within the muscle. Recent data have demonstrated that SC mitochondrial metabolic state is a regulator of both SC differentiation and muscle inflammation [ 42 ]. Whether loss of metabolic control in satellite cells is associated with the loss of SC responsiveness in older septic survivors remains a key knowledge gap.…”