The progressive loss of skeletal muscle mass and strength, a condition known as sarcopenia, is perhaps the most debilitating age-associated alteration. In sarcopenia, muscle strength/power decrease significantly more than muscle mass itself, suggesting that it is the overall quality of the muscle that is affected and not only the size or quantity of muscle. Muscle fatigue occurs when the intended physical activity can no longer be continued or is perceived as involving excessive effort. Unfortunately, many elderly suffer from fatigue at physical efforts far less (i.e. walking) than the efforts that are required to induce fatigue in healthy young people. Force generation in muscle is tightly coupled to the release and subsequent re-sequestering of Ca2+ by the sarcoplasmic reticulum (SR). Dysfunction in the Ca2+ handling process has been strongly implicated in the loss of force production in many fatigue producing situations, and it has been suggested that Ca2+ handling impairment may significantly contribute to skeletal muscle failure in sarcopenia. It is also known that tissue hypoxia is greater in aged muscle, and this may exacerbate the mechanisms contributing to Ca2+ handling failure. We have demonstrated that there is a range of reduced O2 availability that will induce ?metabolic adaptation? to maintain mitochondrial respiration and energy generation (of which Ca2+ handling may require more than 40%!). Lower intracellular O2 levels in aged muscle will result in a more perturbed intracellular milieu, resulting in an impaired muscle function--in part due to negative effects on the Ca2+ handling process. The interplay between O2 availability and Ca2+ handling on skeletal muscle dysfunction in the elderly has not been carefully investigated, and in particular, treatments for this impairment have not been analyzed. The purpose of this proposed research is to use mouse isolated whole muscle and an intact single skeletal muscle fiber to: 1) test a number of hypotheses centered around the notion that cellular O2 (at levels well above those limiting mitochondrial respiration) induce alterations in the intracellular environment that affect Ca2+ handling in aged muscle, thereby leading to an earlier onset of contractile impairment in hypoxia. And most importantly: 2) test treatments and transgenic models which affect different components of the Ca2+ handling process in an attempt to develop therapeutic strategies for combating O2-related Ca2+ handling dysfunction and thereby alleviate some of the muscle impairment in sarcopenia. Our experimental models allow precise control of the extracellular environment and the intracellular environment can be carefully monitored using non-invasive fluorescent imaging techniques. It is the goal of this research project to use our unique single myofiber model to carefully elucidate the mechanisms by which reduced cellular PO2 in aged muscle impairs Ca2+ handling and contractility, and to subsequently develop strategies to reduce frailty associated Ca2+ handling impairments in older subjects.

Public Health Relevance

PROJECT RELEVANCE The relentless loss of skeletal muscle mass and strength, a condition known as sarcopenia, is a hallmark of human aging and has an enormous cost in both monetary terms and in the quality of life of the elderly. It is the goal of this proposed research to assess the mechanisms by which the reduced oxygen availability to working aged muscle impairs the calcium handling and contractile properties of muscle and subsequently to develop strategies to minimize the deleterious effects of these processes in muscle of the elderly.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Muscle and Exercise Physiology Study Section (SMEP)
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Carifi, Emily Foran
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University of California, San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
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Gandra, Paulo G; Shiah, Amy A; Nogueira, Leonardo et al. (2018) A mitochondrial-targeted antioxidant improves myofilament Ca2+ sensitivity during prolonged low frequency force depression at low PO2. J Physiol 596:1079-1089
Nogueira, Leonardo; Trisko, Breanna M; Lima-Rosa, Frederico L et al. (2018) Cigarette smoke directly impairs skeletal muscle function through capillary regression and altered myofibre calcium kinetics in mice. J Physiol 596:2901-2916