A delayed and incomplete healing response following skeletal muscle trauma, such as surgery or injury, is a common clinical phenomena observed in elderly individuals. Such a regenerative deficit is typically a result of increased fibrosis formation, increased intermuscular adipose deposition, decreased myofiber regeneration, and subsequent decreased contractility. The increased fibrosis and adipose formation following injury has been attributed to an increased myogenic-to-fibrogenic and -adipogenic conversion of aged muscle precursor cells (MPCs). Fortunately, age-related declines in skeletal muscle regenerative capacity are potentially reversible, as has been observed following heterochronic pairings (in which the circulatory systems of a young and old animal are joined), gene therapy, and direct growth factor injection in animals. Mechanotransductive pathways, initiated by exercise or electrical stimulation (E-stim) for example, also increase MPC activation and proliferation, and favor myogenesis. In this study, we will investigate whether the muscle macro- and micro-environment can be non-invasively modulated by E-stim to enhance skeletal muscle healing in aged animals.
The specific aims of these studies are: 1. to determine the ability of E-stim, in vitro and in vivo, to restore the regenerative potential of muscle progenitor cells (MPCs) isolated from aged skeletal muscle and 2. to determine the ability of in vivo E-stim to enhance regeneration of aged skeletal muscle following an acute muscle injury, as analyzed using histology and functional testing. The working hypothesis of this proposal is that application of targeted and specific E-stim protocols can improve the healing response to injury in aged animal models at the whole tissue, cellular and signaling levels. Throughout my scientific biography, I have been committed to a career investigating cellular and rehabilitation- based therapies for the improvement of skeletal muscle physiology and functioning. I plan to use the NIH Career Development Award to support my investigations that utilize rehabilitation principles to reverse the effect of age on skeletal muscle function. My mentors and I have designed a career development plan for the accomplishment of four specific goals: 1) To gain an increased understanding of current state of the field of aging from a molecular stand-point, 2) To become skilled in molecular approaches for assessing skeletal muscle and organismal aging, 3) to improve my grantsmanship skills, and 4) to maintain my commitment to training in the responsible conduct of research.

Public Health Relevance

Poor muscle healing after injury can trigger a devastating decline in functional mobility in an aging population. Compelling evidence has demonstrated that rejuvenation of the muscle environment can dramatically improve the healing capacity of aged tissue. The long-term goal of this project is to investigate the use of electrical stimulation to rejuvenate aged skeletal muscle healing and function.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Scientist Development Award - Research & Training (K01)
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National Institute on Aging Initial Review Group (NIA)
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Williams, John
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University of Pittsburgh
Physical Medicine & Rehab
Schools of Medicine
United States
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Distefano, Giovanna; Ferrari, Ricardo Jose; Weiss, Christopher et al. (2013) Neuromuscular electrical stimulation as a method to maximize the beneficial effects of muscle stem cells transplanted into dystrophic skeletal muscle. PLoS One 8:e54922
Kobayashi, Tetsuo; Uehara, Kenji; Ota, Shusuke et al. (2013) The timing of administration of a clinically relevant dose of losartan influences the healing process after contusion induced muscle injury. J Appl Physiol (1985) 114:262-73