Defective branched chain amino acid catabolism impairs exercise capacity and glucose homeostasis in the mouse

Thesis (Ph.D.)--University of Washington, 2019The branched-chain amino acids (BCAAs) leucine, isoleucine and valine, play a central role in substrate metabolism, energetics, and protein synthesis. Although BCAA supplementation is widely used to improve exercise capacity and physical fitness, elevated levels of the BCAAs have been implicated in the development of obesity and metabolic diseases, and the mechanisms governing these conflicting outcomes are still unknown. This work explored the effects of systemically elevated BCAA levels in a mouse model of defective BCAA catabolism (knockout [KO]) on exercise capacity and performance. We studied the impact of BCAAs on three factors of exercise metabolism; the role of BCAAs in regulating glucose and fatty acid utilization in skeletal muscle, the role of downstream intermediates on tricarboxylic acid (TCA) cycle flux during exercise, and the impact of elevated BCAAs on gluconeogenesis during exhaustive exercise. We found that defective BCAA catabolism significantly decreased endurance exercise capacity in the mouse, and this impairment may be due to disruption of glucose homeostasis. Although elevated BCAAs did not significantly impact substrate utilization in the skeletal muscle, increasing glucose utilization in the skeletal muscle through activation of pyruvate dehudrogenase (PDH) caused a further decrease in exercise capacity in KO mice. Exhaustive exercise and prolonged fasting caused a further elevation in systemic BCAA levels in KO mice, and caused a similar depletion in liver and skeletal muscle glycogen levels. Fasted KO mice were unable to increase their blood glucose levels from the glucogenic precursors pyruvate and glutamine, suggesting that elevated BCAAs suppress gluconeogenesis and impair whole body glucose homeostasis. However, elevating blood glucose levels in mice during exercise did not impact exercise performance. These results provide insights on the efficacy of BCAA supplementation on improved exercise performance, however, whether BCAA catabolism is an instigator or merely a symptom of impaired exercise performance, metabolic health, and weight management