Aging is associated with alterations in skeletal muscle energy metabolism, insulin resistance and a higher prevalence of type 2 diabetes mellitus (T2DM). Aging is also associated with a progressive loss of muscle mass and increased adiposity, known as sarcopenic obesity, which leads to mobility limitations and disability. However, the causes of insulin resistance and sarcopenia in humans are not known. This project will provide novel information regarding potential factors underlying both metabolic dysfunction and sarcopenia in aging muscle - namely, mitochondria and the accumulation of intramyocellular lipids. Within this conceptual framework we will help elucidate the biological underpinnings of these two significant health problems related to aging. In addition, we will provide intervention-based evidence to better understand these complex age-related disorders and whether mitochondria or intramyocellular lipids are modifiable targets for improved prevention or treatment strategies for metabolic and muscle dysfunction. Therefore, our overall objectives are to employ highly innovative methods in muscle biopsy specimens in order to determine the functional and clinically relevant consequences of these interventions as well as alterations in several novel biochemical and molecular factors potentially underlying these intervention effects on human skeletal muscle.

Public Health Relevance

Dieting to lose weight may have positive benefits in older, overweight men and women. However, these benefits may come at a cost regarding the loss of muscle tissue. This project will provide unique biochemical and molecular targets in human skeletal muscle underlying the benefits as well as the potential negative consequences of dieting to lose weight in older men and women.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Joseph, Lyndon
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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Distefano, Giovanna; Standley, Robert A; Dubé, John J et al. (2017) Chronological Age Does not Influence Ex-vivo Mitochondrial Respiration and Quality Control in Skeletal Muscle. J Gerontol A Biol Sci Med Sci 72:535-542
Goodpaster, Bret H; Sparks, Lauren M (2017) Metabolic Flexibility in Health and Disease. Cell Metab 25:1027-1036
Summers, Scott A; Goodpaster, Bret H (2016) CrossTalk proposal: Intramyocellular ceramide accumulation does modulate insulin resistance. J Physiol 594:3167-70
Coen, Paul M; Goodpaster, Bret H (2012) Role of intramyocelluar lipids in human health. Trends Endocrinol Metab 23:391-8
Dubé, John J; Allison, Katelyn F; Rousson, Valentin et al. (2012) Exercise dose and insulin sensitivity: relevance for diabetes prevention. Med Sci Sports Exerc 44:793-9
Dubé, J J; Amati, F; Toledo, F G S et al. (2011) Effects of weight loss and exercise on insulin resistance, and intramyocellular triacylglycerol, diacylglycerol and ceramide. Diabetologia 54:1147-56