Jens Frey Halling:
Skeletal muscle mitochondrial function and redox balance is impaired during aging which has been associated with the progression of age-related pathological conditions such as insulin resistance. Exercise training increases mitochondrial oxidative capacity and counteracts both age-related mitochondrial impairments and insulin resistance. The transcriptional co-activator PGC-1α is a key regulator of exercise-induced mitochondrial biogenesis, but the role of PGC-1α in exercise traininginduced regulation of mitochondrial quality control mechanisms beyond biogenesis (such as fission/fusion and autophagy) in skeletal muscle has not been examined.
Therefore, the overall aim of this PhD was to investigate the role of PGC-1α in regulation of mitochondrial function beyond biogenesis in mouse skeletal muscle in response to acute exercise and exercise training during aging, and the concurrent impact on insulin sensitivity. This was addressed in four separate papers and a literature review. The papers employed different transgenic PGC‐1α mouse models to investigate: Acute exercise-induced regulation of autophagy; in situ mitochondrial network structure with aging and exercise training; ex vivo measures of mitochondrial respiration and H2O2 emission with aging and exercise training; and the effect of autophagy inhibition on skeletal muscle mitochondrial function and insulin sensitivity.
The results showed that PGC-1α promoted acute exercise-induced autophagy in mouse skeletal muscle. In addition, aging was associated with fragmentation of mitochondrial networks in mouse skeletal muscle which was reversed by exercise training through a PGC-1α-dependent mechanism. Aging was associated with impaired ADP sensitivity and altered redox balance, independently of changes in mitochondrial content. Skeletal muscle PGC-1α was required for the full exercise traininginduced reversal of age-related intrinsic mitochondrial dysfunction. Age-related mitochondrial dysfunction was not due to impaired basal autophagy flux in aged skeletal muscle, and loss of PGC-1α did not affect autophagy flux. Mitochondrial ADP sensitivity and redox state in mouse skeletal muscle were disrupted by colchicine treatment with concomitant impairment of skeletal muscle insulin sensitivity in aged mice, independently of PGC-1α.
In conclusion, the findings in this PhD thesis indicate that intrinsic mitochondrial function in skeletal muscle is impaired during aging, but this can be prevented or restored by exercise training. The molecular mechanisms behind exercise training-mediated reversal of mitochondrial dysfunction likely include PGC-1α-dependent regulation of mitochondrial network structure. In addition, inhibition of autophagy impairs skeletal muscle insulin sensitivity in aged mice. However, PGC-1α does not seem to be involved in age-related changes in autophagy flux or skeletal muscle insulin resistance.