Identifying novel regulators of mitochondrial biogenesis in human skeletal muscle

Background:

Skeletal muscle in a healthy adult accounts for approximately 40% of total body mass. In addition to its primary tasks of maintaining posture, breathing and locomotion, skeletal muscle also represents an important nutrient store and metabolic regulator. Unlike many organs within the body that reach their capacity for growth and function upon maturity, skeletal muscle maintains high levels of plasticity during adulthood, being highly susceptible to common stressors such as physical activity/inactivity, exercise and diet. Compelling epidemiological data clearly demonstrates that muscle functional capacity is fundamental for health span (1), thus understanding the regulation of skeletal muscle at the cellular level holds tremendous therapeutic potential for health and disease.

Within skeletal muscle, mitochondria are vital energy producing organelles, generating ATP from intracellular substrate stores. Mitochondrial biogenesis is a broad term used to describe an increase in mitochondrial content, function and activity (2). At the cellular level this adaptive response represents an increase in transcriptional activity, increased content (proliferation) and an increase in mitochondrial protein synthesis (2). Whilst it is well established that aerobic exercise is a potent stimulator of skeletal muscle mitochondrial adaptation; the mechanistic basis linking muscle contraction to mitochondrial biogenesis is still poorly understood. This project will seek to translate recent in vitro and rodent based work from our laboratory (3, 4) into human exercise models, to identify novel transcriptional and post-translational regulators of mitochondrial biogenesis in human skeletal muscle.