Altered micronutrient partitioning as a regulator of mitochondrial health in skeletal muscle

University Of Arkansas At Fayetteville, Fayetteville AR

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Abstract

According to the United States Census Bureau and CDC, in 2030 more than 20% of the US population will be >65 years old. With a life expectancy in the US of 78.6 years, Americans are living longer with increased rates of disability; therefore, understanding and managing physical limitations in the aging population becomes integral for enhancing health span and reducing economic burden. One contributor to physical limitations in aging is sarcopenia, which is characterized by loss of skeletal muscle mass and strength. In addition to muscle loss, mitochondrial function declines with age and may precede age-related phenotypes, including sarcopenia. Mitochondrial DNA (mtDNA) encodes 13 proteins that are required for ATP synthesis, and it has been recognized for decades that mutations in mtDNA increase with age, lead to diseases, and occur approximately 100-fold more frequently than in the nuclear genome. Moreover, because mitochondria provide the majority of energy to most cells in the body, mutations or deletions in mtDNA manifest themselves as distinct phenotypes in tissues with high energy demands such as skeletal muscle. In fact, it was recently identified that skeletal muscle samples from aged humans exhibited a 98-fold increase in mtDNA mutation frequency and a 2.5-fold decrease in mtDNA copy number compared to skeletal muscles samples derived from young adults. While mitochondrial DNA mutations increase with aging and are associated with low serum folate and both are suggested to increase skeletal muscle fiber loss and impair muscle function, no research has focused on the metabolic pathway linking the causal relationship. Yet, data from our lab indicates mitochondrial folate-mediated one-carbon metabolism may play a role, as folate depletion results in an increased mitochondrial 3860-bp common deletion in aged mouse gastrocnemius. Furthermore, the accumulation of folate in skeletal muscle in aged mice is lower than young mice even when consuming a folate-adequate diet. Our overall objectives in this application are to 1) establish the relationship between blood values of folate with tissue levels of folate, and 2) determine the effects of folate availability on skeletal muscle mitochondrial integrity and function. This proposal is innovative in concept and approach and will inform on safe and effective nutritional strategies for maintenance of folate levels to maintain optimal mitochondrial function and health across the lifespan.