The Aging Phenomenon, Related with DNA Damage, MMR Deficiency and Oxidative Stress, Has Different Outcomes in Two Species of the Order Chiroptera

Abstract

Divergent Roles for 12/15-Lipoxygenase and 5Lipoxygenase Lipid Metabolic Pathways in Neurogenic Muscle Atrophy Arunabh Bhattacharya, Ryan Hamilton, Carmen Rios, Amanda L Jernigan, Yiqiang Zhang, Marian Sabia, Md M Rahman, Yan Li, Wenbo Qi, and Holly Van Remmen University of Texas Health Science Center at San Antonio, GRECC, South Texas Veterans Health Care System, San Antonio Aging is associated with progressive decline in muscle mass and function which significantly impacts the quality of life in the elderly population. Studies by our group and others have shown that decline in neuromuscular junction integrity (i.e. loss of innervation) during aging plays a causative role in age-related loss of muscle mass and function. However, little is known about the pathways and/or mediators that induce muscle atrophy during age-related loss of skeletal muscle during denervation. We previously showed that muscle atrophy during aging and surgical denervation is associated with increase in the expression of cytosolic phospholipase A2, the rate limiting step for release of arachidonic acid from membranes which then acts as a substrate for lipid metabolic pathways catalyzed by 12/15-lipoxygenase (12/15-LO), 5-lipoxygenase (5-LO) and cyclooxygenase and leads to the generation of bioactive lipid metabolites that are important mediators of inflammation and/or oxidative stress. In this study, we report that the expression and activity of 5and 12/15-LO pathways are significantly elevated in atrophied muscles from denervated mice. While genetic ablation/pharmacological inhibition of 12/15-LO confers protection against denervationinduced muscle atrophy, genetic ablation/pharmacological inhibition of 5-LO tends to increase muscle atrophy. We find that the activation of 12/15-LO pathway during denervation-atrophy increases NADPH oxidase mediated oxidative stress which leads to oxidative damage to lipids and proteins and increased proteolytic degradation by the ubiquitin-proteasome pathway. These findings reveal for the first time divergent roles for 5-LO and 12/15-LO lipid signaling pathways in muscle atrophy during loss of innervation.