Skeletal Muscle Health Protects Vascular Function in Obesity

PROJECT SUMMARY Obesity remains the most persistent threat to cardiovascular health in the United States. Exercise mitigates much of this risk, but the therapeutic benefits of exercise are frequently beyond the capabilities of the aged, the very obese or those with prior injuries. Understanding the mechanisms of the beneficial properties of exercise on the cardiovascular system could identify targets that replicate or enhance the salutary effects of physical exertion. Despite this well-recognized paradigm, targets remain elusive. Prior work from our laboratory has determined that preserving skeletal muscle mass and performance through deletion of myostatin, a negative regulator of muscle growth, improves redox balance and nitric oxide signaling in the vasculature and cardiovascular health in obese mice. This improvement occurs despite no change in physical activity, indicating that the metabolic state of skeletal muscle is an important mechanism underlying the preservation of cardiovascular health. The goal of this application is to determine the mechanisms linking specific improvements in skeletal muscle metabolism with vascular health in obesity. In preliminary data for the current proposal, we have identified three potential mechanisms. The first is that an expanding fat mass in obesity results in increases in CYP1B1 expression in skeletal muscle. CYP1B1 is an extrahepatic monooxygenase that hydroxylates estrogen (and other metabolites) that can cause muscle lipid accumulation. We will test the hypothesis that CYP1B1 is a mediator of skeletal muscle dysfunction and vascular injury in obesity. Secondly, activation of lipogenic pathways results in myosteatosis, the ectopic and inappropriate accumulation of lipids in muscle. Because exercise and deletion of myostatin reduce steatosis in skeletal muscle in parallel with improved vascular health, we will test the hypothesis that resolving myosteatosis by preventing the synthesis of lipids, protects vascular health in obesity. Finally, we have discovered that deletion of myostatin results in the massive upregulation of sarcolipin, a novel micropeptide that uncouples SERCA function to increase mitochondrial fat oxidation. We will test the hypothesis that selective upregulation of sarcolipin in the skeletal muscle of obese mice is a therapeutic strategy to reduce excess lipids and restore cardiometabolic health. We will accomplish these goals using novel, state of the art tools to manipulate gene expression in lean and obese mice and unravel the integrated pathways that undermine cardiovascular function in obesity.