Muscle weakness is a common clinical phenomina observed following bed rest, surgery, cast immobilization and injury or disease. The consequences of loss of muscle strength are far reaching and include decrease of motor control and overall fitness, development of functional limitations and impairment, and long term disability. As such, the objective of this study is to investigate the potential of virus-mediated gene transfer of IGF-1 to guard skeletal muscle from the deleterious impact of disuse or forced inactivity and to accelerate the subsequent recovery in muscle size and strength. For this purpose the left or right hindlimb (randomized) muscles of young adult mice will be injected with a recombinant adeno-associated virus vector for IGF-1. 3 months post-injection, both hindlimbs (injected and control) of the animals will be immobilized in a plaster cast for a period of 2 weeks. After removal of the cast the animals are allowed to reambulate and resume their normal cage activity. Cage restricted levels of weight-bearing activity have been shown to be sufficient to induce muscle regeneration and hypertrophy. Morphometric and functional measurements will be performed bilaterally (injected and control limb) at baseline, 3 months post-injection, following 2 weeks of cast immobilization, during reloading and at several time points during reambulation (2, 4 and 10 weeks). Morphological measures will include fiber cross- sectional area and fiber number, wet weight and protein content. Functional measures (twitch and tetanic force) will be performed in vitro on superfused muscles. The secondary objective of this study is to elucidate the mechanisms by which IGF-1 overexpression modulates muscle size and function under varying loading/activity conditions. For this purpose we will measure IGF-1 peptide levels, in vivo protein synthesis and degradation rates, and markers of muscle regeneration and satellite cell proliferation. We anticipate that the ability to locally manipulate muscle regeneration and hypertrophy during disuse and subsequent rehabilitation will be of great clinical importance. In addition, we anticipate that this study will help elucidate the role of IGF-1 in the regulation of muscle size under varying loading/activation conditions.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD042955-02
Application #
6640637
Study Section
Geriatrics and Rehabilitation Medicine (GRM)
Program Officer
Nitkin, Ralph M
Project Start
2002-02-01
Project End
2006-01-31
Budget Start
2003-02-01
Budget End
2004-01-31
Support Year
2
Fiscal Year
2003
Total Cost
$229,163
Indirect Cost
Name
University of Florida
Department
Other Health Professions
Type
Schools of Public Health
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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Stevens-Lapsley, Jennifer E; Ye, Fan; Liu, Min et al. (2010) Impact of viral-mediated IGF-I gene transfer on skeletal muscle following cast immobilization. Am J Physiol Endocrinol Metab 299:E730-40
Liu, Min; Stevens-Lapsley, Jennifer E; Jayaraman, Arun et al. (2010) Impact of treadmill locomotor training on skeletal muscle IGF1 and myogenic regulatory factors in spinal cord injured rats. Eur J Appl Physiol 109:709-20
Pathare, Neeti; Vandenborne, Krista; Liu, Min et al. (2008) Alterations in inorganic phosphate in mouse hindlimb muscles during limb disuse. NMR Biomed 21:101-10
Stevens, Jennifer E; Liu, Min; Bose, Prodip et al. (2006) Changes in soleus muscle function and fiber morphology with one week of locomotor training in spinal cord contusion injured rats. J Neurotrauma 23:1671-81
Frimel, Tiffany N; Kapadia, Fatema; Gaidosh, Gabriel S et al. (2005) A model of muscle atrophy using cast immobilization in mice. Muscle Nerve 32:672-4
Frimel, Tiffany N; Walter, Glenn A; Gibbs, John D et al. (2005) Noninvasive monitoring of muscle damage during reloading following limb disuse. Muscle Nerve 32:605-12