Abstract 569: Functional Benefits of Muscle PGC-1alpha in Aged Animals

Abstract

Metabolic homeostasis requires a complex network of transcriptional programs. PGC-1 (peroxisome-proliferator-activated receptor-γ coactivator-1) alpha is a potent transcriptional coactivator that coordinates the activation of a large number of nuclear-encoded genes, which, in turn, regulate numerous metabolic processes. Exercise strongly induces muscle PGC-1alpha in both humans and rodents. Over-expression of PGC-1alpha in skeletal muscle activates mitochondrial oxidative metabolism, fast-to-slow fiber-type switching, and neovascularization, leading to markedly increased endurance. In light of these findings, PGC-1alpha has been proposed to protect from age-associated sarcopenia, bone loss, and whole-body metabolic dysfunction, although these findings have been controversial. We therefore comprehensively evaluated muscle and whole-body function and metabolism in 24 month-old transgenic mice that over-express PGC-1alpha in skeletal muscle. We find that the powerful effects of PGC-1alpha on promoting muscle oxidative capacity and protection from muscle fatigability persist in aged animals, although at the expense of muscle strength. However, skeletal muscle PGC-1alpha does not prevent bone loss and in fact accentuates it, nor does it have long-term benefit on whole-body metabolic composition or insulin sensitivity. Interestingly, we see protection from sarcopenia in male animals with over-expression of PGC-1alpha in skeletal muscle but not in female animals. In summary, muscle-specific expression of PGC-1alpha into old age has beneficial effects on muscle fatigability and may protect from sarcopenia in males, but does not improve whole-body metabolism and appears to worsen age-related trabecular bone loss.