Synergistic Effects of Unacylated Ghrelin and Endurance Exercise on Sarcopenia and Mobility Loss - Project Summary/Abstract Sarcopenia, the progressive loss of muscle mass and function, universally impacts the aging population, contributing to loss of mobility and independence in older adults. With the rapid growth of the aging population, there is an urgent need for effective strategies against sarcopenia. Exercise is the most effective intervention that increases muscle mass and function in younger adults, but its benefits are attenuated in older adults due to diminished responses to exercise training. Over the years, several candidate molecules, including metformin, antioxidants, and resveratrol were combined with endurance exercise (EE) in an attempt to increase training- induced benefits; however, these interventions failed to enhance training responses and, in some cases, reduced the positive effects of exercise. Given metformin’s inhibitory effects on mitochondrial respiration and the ability of antioxidants to scavenge signaling molecules in response to exercise, a logical next step is to combine EE with a candidate molecule that specifically enhances mitochondrial bioenergetics and its downstream pathways. A strong such candidate is unacylated ghrelin (UnAG), whose circulating levels are significantly decreased in older adults and mice. Our pilot data provides evidence that UnAG combined with endurance exercise (UnAG+EE) additively increases mitochondrial bioenergetics, while synergistically improving motor coordination, muscle mass and contractile function. Our data also revealed that UnAG activated both shared (i.e., PGC-1α) and distinct (i.e., mTORC2) pathways compared to those triggered by EE alone, suggesting that UnAG+EE may provide synergistic and complementary benefits. Building on our compelling preliminary data, we hypothesized that the combination of UnAG+EE will enhance mitochondrial bioenergetics and preserve NMJ integrity in older mice, providing synergistic protection for sarcopenia. Our specific aims will focus on the effects of UnAG, EE, and UnAG+EE on mitochondrial bioenergetics and oxidative stress (Aim 1), motor neuron cell numbers and inflammation in the spinal cord and neuromuscular junction (Aim 2), and muscle mass, function, and protein quality in skeletal muscle (Aim 3) in older mice. We will also assess additive or synergistic effects of UnAG+EE on key endpoint measures for each aim. Transcriptomic analysis will be performed to identify differentially expressed genes and pathways influenced by our interventions, which can provide essential information for mechanistic investigations in the future. If our results support the hypothesis, UnAG+EE will be the first combination therapy that shows additive or synergistic effects for sarcopenia. UnAG+EE also has great potential for translation, given the established safety of UnAG and its mimetics in humans. Finally, our proposal aligns directly with the current Strategic Directions of the NIA, “Develop effective interventions to maintain health, well- being, and function, while preventing or reducing the burdens of age-related diseases, disorders, and disabilities.
