Dissertation Defense: PERM1-Mediated Metabolic Crosstalk Between the Heart and Skeletal Muscle in Pressure Overload-Induced Heart Failure

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Heart failure is a complex syndrome with high mortality, as nearly 50% of patients die within five years of diagnosis. Among its systemic complications, cardiac cachexia–a condition characterized by severe unintentional weight loss due to cardiac dysfunction–serves as an independent predictor of mortality. The early stage of cachexia involves a vicious cycle between the heart and skeletal muscle driven by metabolic dysregulation; however, its underlying bioenergetics remain unclear. PERM1, a striated muscle-specific regulator of mitochondrial bioenergetics, is highly expressed in the heart and skeletal muscle. We previously demonstrated that PERM1 is downregulated in failing hearts; however, whether its downregulation also occurs in skeletal muscle during the progression of heart failure is unknown. To address this, wild-type mice underwent transverse aortic constriction (TAC) for 8 weeks. Cardiac function and body composition were assessed by echocardiography and NMR, and PERM1 expression and metabolomic profiles were analyzed by Western blotting and gas chromatography-tandem mass spectrometry (GC-MS). TAC reduced systolic function and downregulated PERM1 to a comparable extent in both tissues. Global PERM1 knockout (KO) mice exhibited lean mass loss with an increase in adiposity and no change in body weight, indicating sarcopenic phenotype and not cachectic phenotype. Partial loss of PERM1 in heterozygous mice accelerated systolic decline and mortality and modulated metabolomic programs linked to ketone handling, branched and medium chain fatty acid oxidation, malate-aspartate shuttling, amino acid anaplerosis, nitrogen recycling, and membrane/cofactor biosynthesis. In vitro, PERM1 silencing in C2C12 myotubes induced a compensatory shift toward glycolysis. AAV-PERM1 preserved systolic function and remodeled metabolomes modestly in the heart and robustly in skeletal muscle as compared AAV-GFP controls. In summary, this study provides the first coordinated PERM1 downregulation and distinct metabolic alterations, which may contribute to systemic myopathy. These findings highlight PERM1 as a potential regulator of metabolic crosstalk between the heart and skeletal muscle during the progression of heart failure.