Mitochondrial Function in Muscle Stem Cell Fates

Abstract

Mitochondria are crucial organelles that control cellular metabolism through an integrated mechanism of energy generation via oxidative phosphorylation. Apart from this canonical role, it is also integral for ROS production, fatty acid metabolism and epigenetic remodeling. Recently, a role for the mitochondria in effecting stem cell fate decisions has gained considerable interest. This is important for skeletal muscle, which exhibits a remarkable property for regeneration following injury, owing to satellite cells (SCs), the adult myogenic stem cells. Mitochondrial function is associated with maintaining and dictating SC fates, linked to metabolic programming during quiescence, activation, self-renewal, proliferation and differentiation. Notably, mitochondrial adaptation might take place to alter SC fates and function in the presence of different environmental cues. This review dissects the contribution of mitochondria to SC operational outcomes, focusing on how their content, function, dynamics and adaptability work to influence SC fate decisions.

Keywords: epigenetics; metabolism; mitochondria; myogenic stem cells; satellite cell fates.

FIGURE 1

Mitochondrial function in satellite cell fates. Quiescent satellite cells (SCs) utilize fatty acids through β-oxidation for Oxphos in the mitochondria. Activation of quiescent SCs might potentiate their self-renewal or formation of myogenic progenitor cell (MPC) progeny that undergo proliferation and eventually differentiate as part of myofibers. Mitochondrial metabolism is poorly elucidated in self-renewing SCs, whereas MPCs rely on glycolysis to obtain energy for rapid division. As differentiation progresses, there is increased mitochondrial fission, followed by mitophagy, after which the mitochondria is repopulated by mitochondrial biogenesis and fusion. ROS levels increase as MPCs begin to differentiate.

FIGURE 2

Influence of the micro-environment on mitochondria of quiescent satellite cells. In a healthy, calorie restricted or exercise adapted micro niche, mitochondria from quiescent satellite cells (SCs) operate efficiently, producing Oxphos with very low ROS. This maintains quiescence and effective self-renewal and differentiation. However, mitochondrial adaptations due to metabolic complications as observed in aging, muscle wasting diseases, obesity and type 2 diabetes, lead to fragmented mtDNA, impairment of Oxphos producing capacity, epigenetic alterations and overproduction of ROS that reduce SC self-renewal and differentiation capacity.

FIGURE 3

Mitochondrial role for epigenetic regulation of satellite cell fates. Representation illustrating the involvement of the mitochondria for histone acetylation (Ac) and methylation and of DNA methylation (Me) in the maintenance and progression of SC fates. The tricarboxylic acid (TCA) cycle intermediates citrate, acetyl CoA (Ac CoA) and α ketoglutarate (αKG) as well as FAD oxidized from FADH₂ in the electron transport chain (ETC), are exported from the mitochondria to be used for epigenetic modification of DNA and histones. Acetyl CoA is a substrate of histone acetyltransferases (HATs), αKG is a cofactor for both histone demethylases; Jumonji C domain demethylases (JMJDs) and DNA demethylases ten eleven translocases (TETs) and FAD is a cofactor for lysine specific demethylases (LSDs) that are associated with active transcription. During quiescence, SCs exhibit activated Pax7 due to H3K4me3 modification on the Pax7 promoter. Proliferative myogenic precursor cells (MPCs) contain the repressive histone modification H3K27me3 and DNA methylation at muscle specific gene promoters such as myogenin (Myog). MPCs also contain activation associated histone modifications characterized by augmented acetylation and H3K4me3 on the Myf5 and MyoD promoters. During differentiation, activation and repression associated histone modifications take place for Myog and Pax7 promoters, respectively.