Abstract 407: Defective Branched Chain Amino Acid Catabolism Impairs Exercise Endurance

Abstract

The branched chain amino acids (BCAA), leucine, isoleucine and valine, are essential for mammals, and they play a positive role in exercise capacity, muscle development, and a lean body phenotype. BCAA supplementation is commonly paired with exercise in order to promote muscle growth, increase resistance to fatigue and reduce muscle soreness. Conversely, elevated serum BCAA is strongly and positively correlated with the development of insulin resistance, coronary heart disease, and type II diabetes, and is predictive of patient response to therapeutics and intervention outcomes. We have previously shown that defective BCAA catabolism in mice impaired glucose metabolism in the heart and increased susceptibility to stress-induced cardiac damage. In this study we sought to determine the effects of elevated BCAA levels on skeletal muscle performance and response to exercise training using mouse models with systemically elevated BCAA levels. Here we assess the hypothesis that defective BCAA catabolism negatively impacts exercise capacity and endurance through deregulation of substrate utilization in the skeletal muscle using a mouse model with systemically elevated BCAA levels. Impairment of BCAA catabolism due to the deletion of mitochondrial-localized protein phosphatase 2C (PP2Cm), a key enzyme in activating BCAA catabolism, leads to elevated BCAA levels in mice. To study this, PP2Cm-knock out (KO) mice and their littermate controls were subjected to high-intensity and low-intensity exercise capacity tests via forced treadmill running. PP2Cm-KO mouse has a 20% reduction in exercise capacity. Reduced exercise capacity positively correlated with elevated serum BCAA levels. Additionally, KO animals supplemented with BCAAs demonstrated elevated serum succinate, alanine and glutamate levels, which are metabolic markers of physiological stress. We conclude that the inability to catabolize BCAAs has a negative effect on exercise capacity and endurance.