BCCMA: Recovery of Aged Muscle After Disuse Atrophy (REMEDY): Targeting metabolism to accelerate recovery from disuse atrophy in aged mice

About This Grant

Older Veterans have a greater burden of multi-morbidity compared to the general population, resulting in frequent and re-occurring inpatient hospitalizations. The inability to recover from hospital acquired muscle weakness is linked to hospital readmittance, morbidity, and pre-mature mortality after discharge. Unfortunately, there are no effective strategies to accelerate rehabilitation from disuse muscle atrophy and weakness acquired during hospitalization. Disuse atrophy accelerates age-related changes in muscle composition that may be more relevant to physical performance than simple measures of muscle mass. Our previous VA supported preclinical studies in older mice show that AdipoRon treatment, a pharmacological activator of adiponectin receptors, rejuvenates systemic metabolism and corrects age-related impairments in muscle metabolism, composition, and function. This project will determine if AdipoRon could also be effective in accelerating recovery from disuse atrophy in the context of aging. The specific aims are 1) determine the effectiveness of AdipoRon to stimulate skeletal muscle mitochondria to mitigate disuse atrophy and/or accelerate recovery, 2) define the life-phase impact of AdipoRon on muscle atrophy and recovery focusing on the intersection of metabolism and growth processes. Mice of different ages will be treated with AdipoRon to activate mitochondrial metabolism using a two-phase design: a) during hind limb suspension, b) during recovery. Recovery at the tissue and functional levels will be determined in vivo and ex vivo, quantifying skeletal muscle contractile function, composition, mitochondrial and lipid metabolism, intramuscular adiposity, and fiber shrinkage and fibrosis. Systemic indices include glucoregulatory function, adiposity, and adipokine and inflammatory signaling that will be correlated with tissue restoration and functional performance. A combination of targeted histological approaches and unbiased molecular approaches (transcriptomics, metabolomics, lipidomics, and kinetic proteomics) will define the disuse atrophy and recovery trajectory. Synergy among projects includes dynamics of proteostasis in collaboration with Project 1 and translational systemic indices that inform about muscle health in collaboration with Projects 3 and 4. Clinical insights will be reverse translated and analyzed against a) pathology of disuse atrophy and b) trajectory of recovery without or with AdipoRon treatment. Collectively, these studies will address whether rejuvenating aspects of metabolism during and after hind-limb unloading can help protect against disuse atrophy and expedite recovery. This work is significant given the lack of available therapeutic options to address the problem of impaired recovery following hospital acquired muscle weakness common to older Veterans.