Muscle stem cells (MuSCs) are essential for muscle regeneration, but their function declines with aging 1-4 , neuromuscular disorders 5-8 , and non-genetic muscle-wasting conditions 9 . Their regenerative capacity is also influenced by environmental factors, including dietary changes such as high-fat diets and diabetes 10-12 , impacting their ability to restore muscle integrity. Understanding the mechanisms that regulate MuSC function is thus crucial for developing strategies to preserve muscle health and improve regenerative potential in both physiological and pathological contexts. Recent advances have unveiled a crucial role for mitochondria in controlling MuSC quiescence, fate decisions, and differentiation into myofibers. Several studies have now shown that disruption of mitochondrial function, through genetic or pharmacological means, leads to dysregulation of MuSC functions and impaired myogenic lineage progression. Mitochondrial abnormalities in MuSCs have also been shown to contribute to the loss of regenerative capacity observed in conditions such as aging, sepsis, in myopathies. Together, this evidence and others have sparked great interest for understanding how these organelles regulate MuSC behavior and exploring the therapeutic potential of mitochondria targeted therapies to improve or maintain muscle regeneration. This review aims to provide a comprehensive overview of the role of mitochondria in regulating MuSC quiescence, fate decisions and myogenesis under both normal and diseased conditions. It summarizes current knowledge, highlights existing gaps, and explores emerging areas related to bioenergetic properties and metabolic signaling, mitochondrial network dynamics, quality control, and inter-organelle cross-talk across different MuSC states. It also discusses potential therapeutic strategies targeting mitochondrial function to enhance MuSC regenerative capacity and counteract muscle degeneration.
Khacho et al. (Wed,) studied this question.