She P, Van Horn C, Reid T, Hutson SM, Cooney RN, Lynch CJ. Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism.

Objectives The aim of this study was to examine skeletal muscle mitochondria content, oxidative capacity, and the expression of key mitochondrial dynamics proteins in patients with heart failure with preserved ejection fraction (HFpEF) and to determine potential relationships with measures of exercise performance. Background Multiple lines of evidence indicate that severely reduced peak exercise oxygen uptake (peak VO2) in older patients with HFpEF, is related to abnormal skeletal muscle oxygen utilization. Mitochondria are key regulators of skeletal muscle metabolism, however little is known about how these organelles are affected in HFpEF. Methods Vastus lateralis skeletal muscle citrate synthase activity, and the expression of porin and regulators of mitochondrial fusion were examined in older patients with HFpEF (n=20) and healthy, age-matched controls (n=17). Results In HFpEF patients compared to age-matched healthy controls, mitochondrial content assessed by Porin expression was 46% lower (p-value= 0.01), citrate synthase activity was 29% lower (p= 0.01), and Mfn2 expression was 54% lower (p= <0.001). Expression of Porin was significantly positively correlated with both peak VO2 and 6 minute walk distance (r=0.48, p=0.003 and r=0.33, p=0.05, respectively). Expression of Mfn2 was also significantly positively correlated with both peak VO2 and 6 minute walk distance (r=0.40, p=0.02 and r=0.37, p=0.03 respectively). Conclusion These findings suggest that skeletal muscle oxidative capacity, mitochondrial content, and mitochondrial fusion are abnormal in older patients with HFpEF and may contribute to their severe exercise intolerance.

Increasing dietary protein has been linked to beneficial effects on insulin sensitivity, lean body mass and obesity. Leu or BCAAs have been implicated as the active agents. To address the role of BCAAs in obesity, we used the Crelox system to generate knock out (KO) mice lacking the mitochondrial isoform of branched‐chain aminotransferase (BCATm), which catalyzes the first step in BCAA metabolism. KOs had elevated plasma concentrations even when allowed to choose between BCAA‐free and –containing diets (choice diet). Differences in body weight on the choice diet could be seen after the 7th week of age. After 18 weeks, male KOs exhibited a 10–15% lower body weight, associated with decreased epididymal fat pad mass (~60% loss), decreased adipocyte diameter and generally‐elevated caloric intake (body weight‐adjusted). Rates of oxygen consumption were increased by 32% during the light and dark cycle in the KO mice, suggesting increased energy expenditure. RQs were also increased, suggesting increased reliance on carbohydrate as fuel. Indeed, KOs had lower fasting plasma glucose and insulin as well as large decreases in areas under curve during GTTs and ITTs. Other obesity relevant endpoints were also improved and the animals were robustly resistant to diet‐induced obesity. These findings suggest that BCATm might be a relevant peripheral target for obesity therapy. info:ddbj-emblgenbank/DK053843 (CJL), info:ddbj-emblgenbank/DK062880 (CJL/SMH), DK34738 (SMH)

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