Recent studies have shown that mitochondria play a role in the regulation of myogenesis. Indeed, the abundance, morphology, and functional properties of mitochondria become altered when the myoblasts differentiate into myotubes. For example, mitochondrial mass/volume, mtDNA copy number, and mitochondrial respiration are markedly increased after the onset of myogenic differentiation. Besides, mitochondrial enzyme activity is also increased, suggesting that the metabolic shift from glycolysis to oxidative phosphorylation as the major energy source occurs during myogenic differentiation. Several lines of evidence suggest that impairment of mitochondrial function and activity blocks myogenic differentiation. However, yet little is known about the molecular mechanisms underlying the regulation of myogenesis by mitochondria. Understanding how mitochondria are involved in myogenesis will provide a valuable insight into the underlying mechanisms that regulate the maintenance of cellular homeostasis. Here, we will summarize the current knowledge regarding the role of mitochondria as a potential regulator of myogenesis.
We investigated the expression of the nuclear-encoded genes controlling the mitochondrial properties in the mouse gastrocnemius muscle to gain insight into the mitochondrial biogenesis that occurs during the muscle degeneration/regeneration induced by freezing. In addition, we tested whether the muscle regeneration is affected by pharmacologically blocking the mitochondrial protein synthesis to elucidate the possible involvement of mitochondrial biogenesis in muscle regeneration. The activity of citrate synthase dramatically increased soon after the initial injury when the myoblasts began to differentiate into myotubes, indicating that mitochondrial biogenesis occurs early during the muscle regeneration. At the same time, the expression of mitochondrial biogenesis-related genes including PGC-1β, PRC, NRF-1, NRF-2, TFAM, mtSSB, fission 1, and Lon protease synchronized with that of the myogenic regulatory genes including MyoD and myogenin. The skeletal muscles forced to regenerate in the presence of chloramphenicol to block the mitochondrial protein synthesis were of poor repair with small myofibers and an increased amount of connective tissue. These results suggest that mitochondrial biogenesis activated early during the muscle regeneration and that mitochondrial biogenesis plays a role in muscle regeneration.
To gain insight into the regulation of mitochondrial adaptations to hindlimb unloading (HU), the activity of mitochondrial enzymes and the expression of nuclear-encoded genes which control mitochondrial properties in mouse gastrocnemius muscle were investigated. Biochemical and enzyme histochemical analysis showed that subsarcolemmal mitochondria were lost largely than intermyofibrillar mitochondria after HU. Gene expression analysis revealed disturbed or diminished gene expression patterns. The three main results of this analysis are as follows. First, in contrast to peroxisome proliferator-activated receptor γ coactivator 1 β (PGC-1β) and PGC-1-related coactivator, which were down-regulated by HU, PGC-1α was up-regulated concomitant with decreased expression of its DNA binding transcription factors, PPARα, and estrogen-related receptor α (ERRα). Moreover, there was no alteration in expression of nuclear respiratory factor 1, but its downstream target gene, mitochondrial transcription factor A, was down-regulated. Second, both mitofusin 2 and fission 1, which control mitochondrial morphology, were down-regulated. Third, ATP-dependent Lon protease, which participates in mitochondrial-protein degradation, was also down-regulated. These findings suggest that HU may induce uncoordinated expression of PGC-1 family coactivators and DNA binding transcription factors, resulting in reducing ability of mitochondrial biogenesis. Furthermore, down-regulation of mitochondrial morphology-related genes associated with HU may be also involved in alterations in intracellular mitochondrial distribution.
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