Rita Brookheart, Ph.D. (Year 1)

ABSTRACT

It is well known that muscle dysfunction and impaired exercise tolerance are common co-morbidities of aging and disease. Muscle dysfunction commonly manifests as reduced skeletal muscle mass and disrupted mitochondrial energy metabolism, which 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 mortality. Delaying or preventing muscle dysfunction in aged and diseased populations would improve patient quality of life and lessen disease severity. Several studies have focused on improving muscle health by targeting either skeletal muscle mass loss or impaired mitochondrial metabolism.

Our lab recently identified a gene (S1P) that controls both skeletal muscle mass and mitochondrial metabolism. Furthermore, we found that a mutation in this gene is linked to exercise impairment in a young, female patient (PMID: 31070020). Moreover, our recent report shows that deletion of S1P in skeletal muscle increases muscle mass in young and aged mice and that S1P inhibits mitochondrial metabolism in muscle (PMID: 37002930). This proposal seeks to expand our knowledge of S1P and at the same time to expand the field’s knowledge of the physiology and pathophysiology of aging through Aim 1 – Determine how S1P inhibits muscle mitochondrial metabolism; Aim 2 – Examine how S1P decreases muscle mass; and Aim 3 – Determine whether S1P depletion improves mobility during aging.

The Aims above will be examined using our S1P skeletal muscle-specific knockout mouse strain and an S1P small molecule inhibitor. This strategy will enhance the experimental rigor by using both genetic and pharmacologic approaches and provide proof of concept evidence for a novel small molecule therapeutic approach to maintain muscle mass and prevent mitochondrial dysfunction in aging and disease. 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 dysfunction and impaired exercise tolerance are common co-morbidities of aging and disease; however, the molecular mechanisms responsible for muscle dysfunction in these 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 function and exercise tolerance. This proposal will expand our understanding of this player’s role in muscle and exercise biology and provide essential pre-clinical data necessary to justify subsequent studies to target this gene for the treatment for sarcopenia and exercise intolerance.