Radak, Z. | bioRxiv Science

bioRxiv2024

Organ specificity and commonality of epigenetic aging in low- and high-running capacity rats

BackgroundEpigenetic drift, which are gradual age-related changes in DNA methylation patterns, plays a significant role in aging and age-related diseases. However, the relationship between exercise, epigenetics, and aging and the molecular mechanisms underlying their interactions are poorly understood. The aim of this study was to investigate the relationship between cardiorespiratory fitness (CRF), epigenetic aging, and promoter methylation of individual genes across multiple organs in selectively bred low- and high-capacity runner (LCR and HCR) aged rats. MethodsIn this study, we performed reduced representation bisulfite sequencing (RRBS) on LCR and HCR aged rats, focusing on the hippocampus, heart, soleus muscle, and large intestine samples. We calculated various epigenetic indicators, including rat epigenetic clocks, global mean DNA methylation (GMM), mean methylation entropy (MME), and gene-specific promoter methylation. ResultsEpigenetic clocks, trained on available rat blood-derived RRBS data did not reflect differences in CRF between LCR and HCR rats across all four organs. However, we observed organ specific differences in GMM and MME between LCR and HCR rats. The direction of these differences was the opposite compared to the age-related changes in the rat blood suggesting that a high CRF may mitigate age-related epigenetic changes in an organ-specific manner. Notably the soleus muscle, exhibited the most pronounced differences in promoter methylation due to CRF. We also identified seven genes whose promoter methylation was consistently influenced by CRF in all four organs. Moreover, we found that age acceleration of the soleus muscle was significantly higher compared to the heart and the hippocampus, and significantly lower compared to the large intestine. Finally, we found that the age acceleration was not consistent across organs. ConclusionsOur data suggest that CRF associates with epigenetic aging in an organ-specific manner and regulates the promoter methylation of individual genes in an organ-specific and organ-common manner. Our findings provide important insights into the biology of aging and emphasize the need to validate rejuvenation strategies in the context of the organ-specific nature of epigenetic aging.

physiology↗

bioRxiv2022

PCYT2 controls muscle health and muscle aging

Muscle degeneration is the most prevalent cause for frailty and dependency in inherited diseases and ageing, affecting hundreds of millions of people. Elucidation of pathophysiological mechanisms, as well as effective treatments for muscle diseases represents an important goal in improving human health. Here, we show that phosphatidylethanolamine cytidyltransferase (PCYT2/ECT), the critical enzyme of the Kennedy branch of phosphatidylethanolamine (PE) synthesis pathway, has an essential role in muscle health. Human genetic deficiency in PCYT2 causes a severe disease with failure to thrive and progressive muscle weakness. Pcyt2 mutant zebrafish recapitulate the patient phenotypes, indicating that the role of PCYT2/PE in muscle is evolutionary conserved. Muscle specific Pcyt2 knockout mice exhibited failure to thrive, impaired muscle development, progressive muscle weakness, muscle loss, accelerated ageing, and reduced lifespan. Mechanistically, Pcyt2 deficiency affects mitochondrial bioenergetics and physicochemical properties of the myofiber membrane lipid bilayer, in particular under exercise strain. We also show that PCYT2 activity declines in the aging muscles of humans and mice. AAV-based delivery of PCYT2 rescued muscle weakness in Pcyt2 knock-out mice and, importantly, improved muscle strength in old mice, offering a novel therapeutic avenue for rare disease patients and muscle aging. Thus, PCYT2 plays a fundamental, specific, and conserved role in vertebrate muscle health, linking PCYT2 and PCYT2 synthesized PE lipids to severe muscle dystrophy, exercise intolerance and aging.

genetics↗