Exercise-induced fumarate accumulation: a potential mediator of mitochondrial biogenesis in mammalian skeletal muscle

Endurance exercise is known to induce mitochondrial biogenesis in mammalian skeletal muscles. However, the exact mechanism via which this exercise-induced mitochondria biogenesis occurs remains unclear. Extraneous physical activity induces several adaptive metabolic changes in the skeletal muscle including the activation purine nucleotide cycle (PNC) and utilization of amino acid as fuel sources. These metabolic adaptations are likely to cause accumulation of intra-muscular fumarate that might be a key mediator of exercise-induced mitochondrial biogenesis. This is because high intracellular levels of fumarate cause irreversible succination of Keap1, which leads to activation of nuclear factor erythroid-derived 2-like 2 (NFE2L2, Nrf2) signalling. Activation of Nrf2 signalling in turn is known to play a role in contraction-induced mitochondria biogenesis. Accordingly, it is possible that therapeutic strategies that enhance skeletal muscle fumarate levels might potentially enhance muscle mitochondrial biogenesis, content and overall physical performance.