Adult Muscle Stem Cell Self-Renewal Induced by Endurance Exercise is Mediated by Inhibition of Mitochondrial Oxygen Consumption

Abstract

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. Here, we found that injured muscles from endurance-exercised mice display improved regenerative capacity, demonstrated through higher densities of newly formed myofibers compared to controls, as well as lower inflammation and fibrosis. Enhanced myogenic function was accompanied by an increased fraction of satellite cells expressing self-renewal markers. Control satellite cells had morphologies suggestive of early differentiation, while endurance exercise enhanced myogenic colony formation. The beneficial effects of endurance exercise were associated with satellite cell metabolic reprogramming, including reduced mitochondrial respiration (O₂ consumption) under resting conditions (absence of muscle injury) and increased stemness. During proliferation or activated states (three days after injury), O₂ consumption was equal in control and exercised cells. Surprisingly, inhibition of mitochondrial O₂ 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 to controls. We propose that endurance exercise promotes self-renewal and inhibits differentiation in satellite cells, an effect promoted by metabolic reprogramming and respiratory inhibition, and which is associated with a more favorable muscular response to injury.