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Mitochondria can sense signals linked to changes in energy demand to affect nuclear gene expression. This retrograde signaling pathway is presumed to be involved in the regulation of myoblast proliferation and differentiation. We have investigated the regulation of mitochondrial biogenesis and production of putative retrograde signaling agents [hydrogen peroxide ([H.sub.2][O.sub.2]) and [Ca.sup.2+]] during the cell cycle and the onset of differentiation in L6E9 muscle cells. The biosynthesis of cardiolipin and mitochondrial proteins was mainly achieved in S phase, whereas the expression of mitochondrial biogenesis factors [peroxisome proliferator-activated receptor (PPAR)-[alpha], PPAR-[delta], and neuronal nitric oxide synthase 1] was regularly increased from [G.sub.1] to [G.sub.2]M phase. In agreement with the increase in mitochondrial membrane potential, mitochondria in S and [G.sub.2]M phases have a significantly higher [H.sub.2][O.sub.2] level when compared with [G.sub.1] phase. By contrast, the onset of differentiation was characterized by a marked reduction in mitochondrial protein expression and mitochondrial [H.sub.2][O.sub.2] level. The capacity of mitochondria to release [Ca.sup.2+] in response to a metabolic challenge was significantly decreased at the onset of differentiation. Finally, an increase in calmodulin expression in S and [G.sub.2]M phases and a transitory increase in phosphorylated nuclear factor of activated T cells (NFAT) c3 in S phase was observed. NFATc3 phosphorylation was markedly decreased at the onset of differentiation. Our data point to functional links between the control of mitochondrial biogenesis and the regulation of the level of retrograde signaling agents during the cell cycle and the onset of differentiation in L6E9 muscle cells. mitochondria; myogenesis; reactive oxygen species; skeletal muscle

Abstract Background Duchenne muscular dystrophy is a genetic disease involving a severe muscle wasting that is characterized by cycles of muscle degeneration/regeneration and culminates in early death in affected boys. Mitochondria are presumed to be involved in the regulation of myoblast proliferation/differentiation; enhancing mitochondrial activity with exercise mimetics (AMPK and PPAR-delta agonists) increases muscle function and inhibits muscle wasting in healthy mice. We therefore asked whether metabolic remodeling agents that increase mitochondrial activity would improve muscle function in mdx mice. Methods Twelve-week-old mdx mice were treated with two different metabolic remodeling agents (GW501516 and AICAR), separately or in combination, for 4 weeks. Extensive systematic behavioral, functional, histological, biochemical, and molecular tests were conducted to assess the drug(s)' effects. Results We found a gain in body and muscle weight in all treated mice. Histologic examination showed a decrease in muscle inflammation and in the number of fibers with central nuclei and an increase in fibers with peripheral nuclei, with significantly fewer activated satellite cells and regenerating fibers. Together with an inhibition of FoXO1 signaling, these results indicated that the treatments reduced ongoing muscle damage. Conclusions The three treatments produced significant improvements in disease phenotype, including an increase in overall behavioral activity and significant gains in forelimb and hind limb strength. Our findings suggest that triggering mitochondrial activity with exercise mimetics improves muscle function in dystrophin-deficient mdx mice.

Mitochondria can sense signals linked to changes in energy demand roexpression. This retrograde signaling pathway is presumed to be affect nuclear gene involved in the regulation of myoblast proliferation and differentiation. We have investigated the regulation of mitochondrial biogenesis and production of putative retrograde signaling agents [hydrogen peroxide (H2O2) and Ca2+] during the cell cycle and the onset of differentiation in L6E9 muscle cells. The biosyinthesis of cardiolipin and mitochondrial proteins was mainly achieved in S phase, whereas the expression of mitochondrial biogenesis factors [peroxisome proliferator-activated receptor (PPAR)-α, PPAR-δ, and neuronal nitric - oxide synthase I]was regularly increased from G1 to G2M phase. In agreement with the increase in mitochondrial membrane potential, mitochondria in S and G2M phases have a significantly higher H2O2 level when compared with H2O2 phase. By contrast, the onset of differentiation was characterized by a marked reduction in mitochondrial protein expression and mitochondrial H2O2 level. The capacity of mitochondria to release Ca2+ in response to a metabolic challenge was significantly decreased at the onset of differentiation. Finally, an increase in calmodulin expression in S and G2M phases and a transitory increase in phosphorylated nuclear factor of activated T cells (NFAT) c3 in S phase was observed. NFATc3 phosphorylation was markedly decreased at the onset of differentiation. Our data point to functional links between the control of mitochondrial biogenesis and the regulation of the level of retrograde signaling agents during the cell cycle and the onset of differentiation ir L6E9 muscle cells. [ABSTRACT FROM AUTHOR]