Influence of Exercise on Proteolysis-Related Markers of Cardiac, Renal, and Endothelial Dysfunction

<h4>Introduction</h4>The effects of aerobic physical activity on proteolysis-related markers of cardiovascular, kidney, and endothelial dysfunction, such as asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), have not been well studied. Our goal was to investigate the correlation between exercise and the levels of proteolysis-related markers by examining the production of ADMA and SDMA across multiple tissues and between sexes.  Methods: We analyzed publicly available data from the Molecular Transducers of Physical Activity Consortium (MoTrPAC), which included previously collected multi-omic profiling of Fischer 344 rats after progressive treadmill training. Analysis of ADMA/SDMA was performed using untargeted hydrophilic interaction liquid chromatography<i> </i>(HILIC)-positive mass spectrometry. Gene expression of ADMA/SDMA producers (protein arginine methyltransferases (PRMTs)) and proteasome-related <i>PSMC</i> genes was examined via RNA-seq in skeletal muscle (gastrocnemius), kidney, liver, adipose tissue, plasma, heart, and small intestine tissue. In cohorts of 50 or 60 mice, data were analyzed over one, two, four, and eight weeks post training and compared to sedentary controls.<h4>Results</h4>Composite ADMA/SDMA levels in brown adipose rose significantly in females and to some extent in males. ADMA and SDMA levels decreased in the small intestine in both sexes, while kidney SDMA rose in males and slightly in females. SDMA also increased transiently in female skeletal muscle. RNA-seq revealed sex-specific changes in proteasome-related <i>PSMC</i> gene expression, including upregulation in female kidney and downregulation in male liver and adipose tissue. PRMT expression decreased in male blood, and PRMT 1-3 trended upward in male brown adipose.<h4>Conclusion</h4>These findings suggest that exercise induces complex tissue- and sex-specific patterns of proteolysis and methylarginine regulation, showing potential associations related to the metabolic benefits of physical activity.