Coordinated changes in mitochondrial function and biogenesis in healthy and diseased human skeletal muscle

We examined the transcriptional signaling cascade involved in the changes of initochondrial biogenesis and mitochondrial function of skeletal muscle and of the exercise capacity of humans in response to long-term physical activity and chronic heart failure (CHF). Biopsy samples of vastos lateralis muscle were obtained from 18 healthy subjects with different fitness levels (assessed by maximal oxygen uptake, VO₂ peak). We compared 9 sedentary subjects with 10 CHF patients undergoing transplantation. Muscle oxidative capacity was measured in permeabilized fibers (Vmax). Transcript levels of target genes were quantified by RT-PCR. In healthy subjects, VO₂ peak was linearly related to Vmax (P<0.01) and to the gene expression of initochondrial proteins and of the coactivator PGC-1 and its downstream transcription factors. A coordinate increase in PGC-1α and mRNA levels of proteins involved in degradation, fusion, and fission of mitochondria was observed associated with calcineurin activation. Despite decreased VO₂ peak, in CHF patients skeletal muscles showed preserved Vmax in accordance with preserved markers and transcription factors of mitochondrial biogenesis and dynamics, with no calcineurin activation. The results provide strong support for a central role for PGC-1α and calcineurin activation in mitochondrial biogenesis in healthy and diseased human skeletal muscles. - Garnier, A., Fortin, D., Zoll, J., N'Guessan, B., Mettauer, B., Lampert, E., Veksler, V., Ventura-Clapier, R. Coordinated changes in mitochondrial function and biogenesis in healthy and diseased human skeletal muscle.