Rita Brookheart, Ph.D. (Year 1 and 2)
FINAL REPORT
Muscle dysfunction and impaired exercise tolerance are common co-morbidities of aging. This aging-associated muscle dysfunction manifests as reduced skeletal muscle mass and a persistent decline in muscle metabolism. Loss of muscle mass and metabolic ability can have detrimental effects on patient mobility and independence, as well as increase the risk of debilitating falls, the need for long-term care, and contribute to mortality. Delaying or preventing muscle dysfunction in aging populations would improve patient quality of life and lessen disease severity. Yet, the molecular mechanisms responsible for muscle dysfunction in these populations are not completely understood — meaning that therapeutics for effectively combating and potentially even preventing muscle dysfunction are lacking.
Our lab recently identified Site-1 Protease (S1P) as a regulator of both skeletal muscle mass and mitochondrial metabolism. Furthermore, we found that in humans, S1P is linked to exercise impairment and mitochondrial dysmorphology (PMID: 31070020). Our recent report shows that deletion of S1P in skeletal muscle increases muscle mass in aged mice and that S1P suppresses muscle mitochondrial metabolism (PMID: 37002930). In year 1 of the award period, we generated data showing that S1P is a key regulator of energy production during muscle growth — suggesting a mechanism whereby mitochondrial metabolism controls muscle size. Year 2 of the award period is focused on (a) defining the mechanism(s) by which S1P regulates metabolism to control muscle size and (b) examining the pathological significance of this mechanism in age-associated muscle loss. Because decreased muscle mass and impaired mitochondrial metabolism are hallmarks of many disease states (i.e., muscular dystrophy, obesity, chronic kidney disease, etc), findings from this proposal may be applicable to several chronic and debilitating human diseases.
Lay Summary
Muscle loss and impaired muscle energy production are common co-morbidities of aging; however, the molecular mechanisms responsible for muscle loss and declines in metabolism in aging populations are not clearly understood — meaning that therapeutics for effectively combating and potentially preventing muscle dysfunction are lacking. Our lab has identified a molecular player that controls both muscle size and metabolism. During Year 1 of the Longer Life Foundation Award, we discovered that muscle size is partly controlled by muscle metabolism (manuscript in preparation). During Year 2 of the award, we will delineate the mechanism by which muscle metabolism controls muscle size and test the efficacy of targeting this mechanism to improve age-associated exercise intolerance and immobility. Completion of this work will expand the field’s knowledge of the physiology and pathophysiology of aging and our pre-clinical discoveries will be applicable to several chronic and debilitating human diseases that also result in impaired muscle mass and metabolism (i.e., cancer, muscular dystrophy, obesity, chronic kidney disease).