BCCMA: Recovery of Aged Muscle After Disuse Atrophy (REMEDY): Targeting energetics and proteostasis in recovery from disuse atrophy

The aging Veteran population has more frequent inpatient hospitalizations than non-Veteran populations. In older Veterans there is an inability to fully recover muscle mass and function after hospital-acquired weakness. The consequence of repeated periods of disuse is a hastening of the progression to disability or frailty for older Veterans. We hypothesize that anticipatory and/or early interventions are critical to maintain muscle mass and function in older Veterans. To address this hypothesis, our specific aims are to: 1) use pre-clinical models to understand biological mechanisms of failed regrowth and potential therapeutic approaches, 2) leverage precision medicine and phenotyping to predict the onset and identify risks and underlying etiology of hospital- acquired weakness in high risk Veterans with multiple morbidities, and 3) determine clinically viable methods of characterizing and monitoring disuse muscle atrophy and its impact on physical functioning and resilience. Studies of old muscle have focused on increasing muscle protein synthesis to accelerate recovery after disuse. However, our studies have found that protein synthesis is not impaired in old muscle and that other protein quality control (i.e., proteostatic) mechanisms fail in old muscle. Based on our findings and those of others, we know that there is impaired mitochondrial bioenergetic capacity in aged skeletal muscle, which gets worse during disuse atrophy. In Project 1 of REMEDY, we hypothesize that the lack of functional recovery following disuse-induced atrophy in older animals is related, in part, to a reduction in mitochondrial bioenergetics which contributes to an inability to maintain proteomic homeostasis (i.e., proteostasis) in skeletal muscle. To test this hypothesis, we have two Specific Aims: 1) Determine how aerobic and skeletal muscle oxidative capacity impacts proteostatic mechanisms and recovery from disuse, and 2) Determine if improving aerobic and skeletal muscle oxidative capacity in older rats leads to better recovery of muscle mass and function following disuse. To address these specific aims, we will use the high-capacity/low-capacity runner (HCR/LCR) rat model and the high response/low response to training (HRT/LRT) rat model. These models allow us to independently test the impact of differences and changes in aerobic mitochondrial aerobic capacity on maintaining muscle proteostasis and improving recovery from disuse atrophy. For our experiments we will use the well-established tail suspension model to examine the effects of hindlimb unloading (HU) and reloading (RE) after HU. We will perform a comprehensive examination of bioenergetics, proteostatic, morphometric, and functional outcomes of multiple hindlimb muscles at baseline, after HU and during RE. Innovation in the project stems from the use of HCR/LCR and HRT/LRT rat models to test differences and changes in mitochondrial bioenergetic function. In addition, we use innovative tracer-based proteomic analyses that we have developed with further mitochondrial characterization using methods developed by our colleagues in Projects 2 and 3. We expect that the greater aerobic and mitochondrial capacity of HCR compared to LCR will be associated with better proteostatic maintenance as evident by fewer protein aggregates during the recovery period, less accumulation in aggregates of proteins tagged for autophagic or proteasomal breakdown, less ER stress, and less inflammation. We also expect that the greater increases in aerobic capacity of HRT compared to LRT following exercise training will result in greater improvements in the same proteostatic mechanisms. Accomplishing this study will determine if mitochondrial bioenergetic capacity is a potential target to improve recovery after disuse atrophy in aging Veterans. In addition, our project contributes to the larger REMEDY project by providing a critical translational intermediate to test potential treatments for clinical implementati Project Number: 1I01BX006508-01A1 | Fiscal Year: 2025 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: Sue Bodine (+1 co-PI) | Institution: OKLAHOMA CITY VA MEDICAL CENTER, OKLAHOMA CITY, OK | Activity Code: I01 | Study Section: Special Emphasis Panel[ZRD1 CAMM-P (01)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11050314