PDH‐mediated metabolic flow is critical for skeletal muscle stem cell differentiation and myotube formation during regeneration in mice

Abstract

Skeletal muscle satellite cells (SMSCs), the major stem cells responsible for the regeneration of skeletal muscle, are normally cell cycle arrested but differentiate to generate myocytes upon muscle damage, forming new myofibers along with self‐renewing stem cells in preparation for subsequent injury. In this study, we investigated which factors stimulate the proliferation and differentiation of SMSCs and found that pyruvate, the end product of glycolysis, stimulates their differentiation. Pyruvate antagonizes the effects of hypoxia on preferential self‐renewal of SMSCs through dephosphorylation or activation of pyruvate dehydrogenase (PDH), which mediates opening of the gateway from glycolysis to the tricarboxylic acid (TCA) cycle by producing acetyl coenzyme A from pyruvate. PDH kinase 1, highly expressed under hypoxia, is down‐regulated under normoxic conditions, leading to an increase in dephosphorylated PDH. Conditional deletion of PDH in SMSCs affects cell divisions generating myocytes and subsequent myotube formation, inefficient skeletal muscle regeneration upon injury, and aggravated pathogenesis of a dystrophin‐deficient mouse model of Duchenne muscular dystrophy. Thus, the flow from glycolysis to the TCA cycle mediated by PDH plays a pivotal role in the differentiation of SMSCs, which is critical for the progression of skeletal muscle regeneration.—Hori, S., Hiramuki, Y., Nishimura, D., Sato, F., Sehara‐Fujisawa, A. PDH‐mediated metabolic flow is critical for skeletal muscle stem cell differentiation and myotube formation during regeneration in mice. FASEB J. 33, 8094–8109 (2019). http://www.fasebj.org

Mitochondrial Function in Muscle Stem Cell Fates

“…Pluripotent and some adult stem cells have devised this method to inhibit mitochondrial Oxphos and enhance glycolysis to sustain rapid proliferation (Folmes et al, 2011;Takubo et al, 2013). Although not much is known about regulation of MPCs by Pdk, it was shown that in hypoxia or glucose deprivation, MPCs have higher Pdk activity to support enhanced glycolysis (Abbot et al, 2005;Hori et al, 2019).…”

“…Despite this shortcoming the past few years have witnessed mitochondrial function linked to dictating SC fate determination, whether to maintain quiescence, become activated, self-renew or commit to differentiate. Importantly, mitochondrial energy output is associated with SC functional outcomes (Lyons et al, 2004;Folmes et al, 2012;Ryall et al, 2015b;Hori et al, 2019). Besides harvesting energy, mitochondria also have other essential functions linked to SC fate decisions.…”

Stimulating pyruvate dehydrogenase complex reduces itaconate levels and enhances TCA cycle anabolic bioenergetics in acutely inflamed monocytes

“…Investigations by many laboratories over the past several decades emphasized the integral role of the mitochondrial pyruvate dehydrogenase complex (PDC) in regulating fuel metabolism and organismal homeostasis in health and during both physiologic and pathologic stress . Under aerobic conditions, PDC catalyzes the rate‐determining step in aerobic glucose oxidation by irreversibly decarboxylating glycolytically derived pyruvate to acetyl coenzyme A (acetyl‐CoA), which condenses with oxaloacetate to form citrate in the tricarboxylic acid (TCA) cycle.…”

PDH Mediated Mitochondrial Respiration Controls the Speed of Muscle Stem Cell Activation in Muscle Repair and Aging

“…PDH-regulated flux of pyruvate into the TCA cycle has been shown to be critical for MuSC differentiation and tissue regeneration 28 . Defective MuSC mitochondrial function results in impaired tissue regeneration 29 and MuSCs with greater mitochondrial content and oxidative phosphorylation are associated with increased capability of initiating myogenic colonies 22 .…”

“…Overall, numerous studies have identified a positive correlation between MuSC oxidative capacity and several aspects of MuSC function including cell number and muscle regenerative activity [22][23][24] . Several recent reports have delineated mechanisms that connect key tricarboxylic acid (TCA) cycle intermediates with transcriptional and epigenetic changes important for the function of MuSCs in muscle regeneration [25][26][27][28][29] . Indeed, cellular metabolism has been linked to quiescence, self-renewal, and differentiation function in other tissue-specific stem cell systems as well [30][31][32][33] .…”