Molecular regulation of the adaptive response to exercise in human skeletal muscle

This thesis examined the molecular regulation and metabolic consequences of human skeletal muscle mitochondrial adaptations to exercise. The transcriptional co-activator peroxisome proliferator-activated receptor gamma co-activator (PGC)-1alpha has emerged as a critical regulator of exercise-induced mitochondrial) biogenesis and has been implicated in the pathogenesis of metabolic-related diseases such as type 2 diabetes (T2D). The mechanisms of how PGC-1alpha might regulate the muscle adaptive response to exercise are not well defined. At rest, the majority of PGC-1alpha was detected in cytosolic fractions prepared from human skeletal muscle biopsy samples. In response to both acute endurance (90 min ∼65% maximal oxygen uptake [VO2peak]) and high-intensity interval exercise (4 x 30-s "all-out" Wingate tests), there was an increase in nuclear PGC-1alpha abundance yet no change in total PGC-1alpha protein. Acute exercise increased the activation of cytosolic p38 mitogen activated protein kinase (p38 MAPK) and 5'-AMP activated protein kinase (AMPK), which are both proposed activators of PGC-1alpha. The increase in nuclear PGC-1alpha after interval exercise also coincided with increased mRNA expression of mitochondrial genes. Two weeks of low-volume high-intensity interval training (HIT), consisting of 6 sessions of 8-12 x 1-min ∼100% VO2peak; increased. nuclear PGC-1alpha, markers of skeletal muscle mitochondrial content, and exercise performance in young, healthy men. A similar low-volume HIT protocol (6 sessions of 10 x 1-min ∼95% VO2peak) improved mitochondrial capacity, functional performance, and glycemic regulation in individuals with T2D and pre-diabetes but had no effect on nuclear or total PGC-1alpha protein content. These findings indicate that acute exercise may activate mitochondrial biogenesis by a mechanism involving increased nuclear PGC-1alpha abundance. Two weeks of practical low-volume HIT is an effective strategy to improve mitochondrial capacity and glycemic regulation in individuals with, and at risk for, T2D, but a sustained increase in PGC-1alpha did not appear to be required.