Mechanisms of Muscle Adaptations in Aging and Exercise

/ABSTRACT The United States is experiencing a significant demographic shift, with the number of older adults projected to increase by 18 million in the next decade, reaching 90 million by 2050. This surge will transform healthcare needs and place considerable strain on social and economic systems, particularly due to age-related health challenges such as sarcopenia. Sarcopenia is associated with increased risks of disability, falls, hospitalization, nursing home admissions, impaired mobility, and early mortality. Despite these serious implications, there are no FDA- approved drugs for sarcopenia, and not all aging individuals can exercise effectively to counter it. Our recent data suggest that the RNA-binding protein human antigen R (HuR or ELAV-like protein 1) may serve as a novel, age-dependent mediator of exercise-induced adaptations and regulate the content of myosin binding protein H (MyBP-H). We found that HuR activity varies with age and parallels positive muscle adaptations following eccentric exercise training in mice. Additionally, HuR-deficient mice exhibited significant protection from strength deficits typically observed after eccentric contraction-induced injury, without compromising other functional parameters. Proteomic analysis revealed that several proteins regulated by training were also regulated by HuR deletion, with MyBP-H being the most significantly upregulated. Furthermore, a novel small molecule inhibitor of HuR (KH-3) protected muscle from strength loss, similar to training or genetic deletion of HuR. This proposal aims to demonstrate that age-dependent regulation of HuR and MyBP-H dictates how skeletal muscle responds to eccentric exercise training. We hypothesize that HuR-dependent expression of MyBP-H is a primary molecular mechanism contributing to exercise-induced adaptations in skeletal muscle. This study will systematically test this hypothesis and bridge basic biology to potential therapeutic applications. Aim 1: Establish if HuR mediates skeletal muscle adaptations to exercise. We will use loss-of-function and gain-of-function mouse models, in addition to a pharmacological inhibitor of HuR RNA-binding. Aim 2: Identify the mechanisms by which HuR activity regulates skeletal muscle adaptations to exercise and MyBP-H expression. We will investigate how changes in HuR activity influence gene expression using high-throughput techniques and specific in vitro methodologies. Aim 3: Determine if MyBP-H content protects skeletal muscle from exercise-induced injury. We will manipulate MyBP-H expression using genetic depletion and overexpression in mice. We anticipate that increasing MyBP-H content, facilitated by inhibiting HuR activity, will enhance the muscle's ability to resist and adapt to exercise-induced injury. This work is timely and innovative, filling a critical gap in our understanding of how skeletal muscle adapts to exercise training, particularly in an age-dependent manner. By combining genetic and pharmacological models with focused analysis of cellular and molecular mechanisms, we aim to identify new strategies to enhance the resiliency and health span of aging muscle. Project Number: 1R01AG097530-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Cory Baumann | Institution: OHIO UNIVERSITY ATHENS, ATHENS, OH | Award Amount: $588,701 | Activity Code: R01 | Study Section: Skeletal Muscle and Exercise Physiology Study Section[SMEP] View on NIH RePORTER: https://reporter.nih.gov/project-details/11366250