Jens Frey Halling - Mitochondrial quality control in aging and T2D: effect of exercise and role of PGC-1α

Skeletal muscle mitochondrial function is impaired in conditions of aging and type 2 diabetes mellitus (T2DM) suggesting that diminished skeletal muscle mitochondrial oxidative capacity is linked to the pathogenesis of aging- and lifestyle-related diseases. Therefore, understanding the regulatory mechanisms responsible for the aging- and T2DM-related decline in mitochondrial oxidative capacity in skeletal muscle is crucial in developing therapeutic and lifestyle-related strategies to maintain skeletal muscle metabolic function in these conditions.

Mitochondrial quality is regulated by mitochondrial biogenesis as well as maintenance of the dynamic mitochondrial network and removal of damaged mitochondria. Exercise training promotes health and has long been recognized as a powerful stimulus for mitochondrial biogenesis in skeletal muscle.

However, exercise training-induced regulation of the mitochondrial reticulum (fission/fusion) and autophagic removal of damaged mitochondria (mitophagy) has received little attention. The transcriptional coactivator PGC-1α has emerged as a key regulator of exercise-induced mitochondrial biogenesis and has been implicated in the skeletal muscle mitochondrial deficiency observed in aging and T2DM.

Recent studies have indicated that PGC-1α is also involved in the regulation of mitochondrial fission/fusion and mitophagy. However, the role of PGC-1α in exercise training-induced coordinated regulation of mitochondrial quality control mechanisms in aging and T2DM has not been investigated.

Therefore, the overall aim of this PhD project is to investigate the possible novel role of PGC-1α in coordinately regulating mitochondrial quality control mechanisms in response to acute exercise and exercise training in mouse and human skeletal muscle in the context of aging and T2DM.