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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AG039477-02
Application #
8335492
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Williams, John
Project Start
2011-09-30
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$108,450
Indirect Cost
$8,033
Name
University of Pittsburgh
Department
Physical Medicine & Rehab
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Stearns-Reider, Kristen M; D'Amore, Antonio; Beezhold, Kevin et al. (2017) Aging of the skeletal muscle extracellular matrix drives a stem cell fibrogenic conversion. Aging Cell 16:518-528
Zhang, Changqing; Ferrari, Ricardo; Beezhold, Kevin et al. (2016) Arsenic Promotes NF-?b-Mediated Fibroblast Dysfunction and Matrix Remodeling to Impair Muscle Stem Cell Function. Stem Cells 34:732-42
Ambrosio, Fabrisia; Brown, Elke; Stolz, Donna et al. (2014) Arsenic induces sustained impairment of skeletal muscle and muscle progenitor cell ultrastructure and bioenergetics. Free Radic Biol Med 74:64-73
Avin, Keith G; Coen, Paul M; Huang, Wan et al. (2014) Skeletal muscle as a regulator of the longevity protein, Klotho. Front Physiol 5:189
Garciafigueroa, D Yesica; Klei, Linda R; Ambrosio, Fabrisia et al. (2013) Arsenic-stimulated lipolysis and adipose remodeling is mediated by G-protein-coupled receptors. Toxicol Sci 134:335-44
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
Ambrosio, Fabrisia; Fitzgerald, G Kelley; Ferrari, Ricardo et al. (2012) A murine model of muscle training by neuromuscular electrical stimulation. J Vis Exp :e3914
Ambrosio, Fabrisia; Tarabishy, Ayman; Kadi, Fawzi et al. (2011) Biological basis of exercise-based treatments for musculoskeletal conditions. PM R 3:S59-63
Ambrosio, Fabrisia; Wolf, Steven L; Delitto, Anthony et al. (2010) The emerging relationship between regenerative medicine and physical therapeutics. Phys Ther 90:1807-14

Showing the most recent 10 out of 12 publications