The potent driver of gene expression, PGC-1 alpha, known for its role in energy balance and metabolism, appears critical to the stability of skeletal muscle, a new study in mice reports. The findings, from the lab of Bruce Spiegelman, where PGC-1 alpha’s role in mitochondrial function was first identified, offer insight into the mechanisms of skeletal muscle dysfunction. The study appears in the Oct. 12 Journal of Biological Chemistry.
Because a whole-body knockout of PGC-1 alpha (short for peroxisome proliferator–activated receptor gamma coactivator 1 alpha) results in an indistinct mix of disorders in mice, the researchers ablated the transcriptional coactivator only in skeletal muscle. PGC-1 alpha emerged as pivotal for maintenance of muscle fiber composition. The researchers found that the knockouts had a reduced number of oxidative type I and IIa muscle fibers and an increase in glycolytic IIx and IIb, fast-twitch fibers that quickly lose energy.
“Type I and IIa fibers, which are the most oxidative fibers, give muscles exercise tolerance and reduce fatigue ability,” said Spiegelman, HMS professor of cell biology at Dana–Farber Cancer Institute.
The mice lacking PGC-1 alpha in their skeletal muscle exhibited reduced endurance compared with control mice and increased muscle fiber injury (along with signs of regeneration). Expression levels in the skeletal muscle declined for mitochondrial genes, necessary for energy production, and for genes that support detoxification of reactive oxygen species, which can damage muscle fibers. Muscle injury in the knockouts rose markedly after physical activity. One demonstration of the decline in physical capacity for the knockouts was a test of muscle grip strength that showed a 60 percent drop in performance compared with control mice.
Since PGC-1 alpha also regulates genes involved in plasticity of the postsynaptic neurosmuscular junction, the knockouts had a lower number of acetylcholine clusters on muscle fiber membranes, suggesting the fibers might be insufficiently innervated.
Spiegelman and his colleagues observed increased levels of the cytokines IL-6 and TNF-alpha in the blood; the rise of TNF-alpha accompanied the increase in muscle fiber damage after exercise. TNF-alpha is known to cause inflammatory myopathies in rodent models and human patients. So the experimental mice may have harbored increased systemic inflammation, a strong promoter of skeletal muscle wasting.
“PGC-1 alpha appears to mediate almost every known effect of exercise on muscle,” Spiegelman said. “We hope we can use it in a way that will be therapeutically beneficial.”
