This R03 proposal is complementary to PI?s K01-award in which metabolic consequences for the lack of skeletal muscle phosphatidylethanolamine (PE) synthesis are being investigated. While the K01 proposal elucidates the role of skeletal muscle PE synthesis that occurs at endo/sarcoplasmic reticulum, the focus of this R03 application is on skeletal muscle mitochondrial PE synthesis that is mediated by an enzyme phosphatidylserine decarboxylase (PSD). Low aerobic capacity is the strongest predictor for all-cause mortality. Skeletal muscle mitochondria are the largest contributors for aerobic metabolism, whose mass exhibits tremendous plasticity in response to exercise training. While molecular mechanisms that mediate syntheses of mitochondrial proteins are well-described, there are no reports that describe how exercise may induce syntheses of mitochondrial structural lipids in skeletal muscle. Our preliminary experiments showed that exercise training induced an increase in skeletal muscle PSD, and its absence in vitro resulted in reduced aerobic capacity that was likely attributable to a reduction in mitochondrial complex II activity. To examine the role of muscle mitochondrial PE synthesis in vivo, mice with skeletal muscle-specific knockout of PSD (PSD- MKO) were generated. In this proposal, we will test the hypothesis that skeletal muscle mitochondria PE synthesis is essential for complex II activity, whose absence results in mice that have low exercise capacity that are more prone to developing metabolic diseases. Data from these studies will provide insights into the role that mitochondrial phospholipid biosynthesis has on skeletal muscle respiratory capacity and whole-body metabolic health.
Low aerobic capacity is the strongest predictor of premature death. Findings from these studies may lead to novel therapeutic approaches to increase aerobic capacity and prevent development of complex diseases.
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