Muscle weakness, injury and inflammation are important obstacles to normal locomotory function in individuals subjected to periods of muscle unloading followed by normal loading. These defects are expected to acquire increased importance in health care of an aging population, in which periods of convalescence can entail prolonged bed rest followed by attempts to regain normal ambulation. The design of optimal preventative or therapeutic treatments to minimize the muscle defects that arise upon reloading will rely upon identifying the factors that contribute to muscle damage during this reloading period. Our findings support the view that myeloid cells contribute to promoting injury and repair during muscle reloading. We hypothesize that neutrophils promote injury to reloaded muscle via free radical mediated events. Furthermore, we propose that the reduction in the expression of nitric oxide synthase (NOS) during muscle unloading renders muscle susceptible to neutrophil-mediated damage, because NO can normally protect muscle from damage by free radicals. Finally, we hypothesize that macrophages participate in muscle repair, so that interventions that affect their presence or activity in muscle can influence the repair process. In the study proposed here, we will test our hypothetical model of myeloid cell function in muscle injury and repair following modified muscle use. We will use mouse hindlimb suspension followed by reloading to induce injury and repair caused by modified muscle use, and assess the effects of depleting neutrophils or macrophages from the animals prior to reloading. We will also examine muscle injury and repair during reloading in transgenic mice that are null mutants or over-expressers of enzymes that generate specific molecules that are implicated in promoting muscle injury or protecting muscle from injury by myeloid cells. The results of the investigation proposed here will provide the first experimental data on the role of myeloid cells in muscle injury and repair following modified use. Those findings can indicate new therapeutic approaches to improving muscle function during muscle reloading following periods of reduced loading.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR047855-04
Application #
6789988
Study Section
Special Emphasis Panel (ZRG1-SSS-3 (04))
Program Officer
Nuckolls, Glen H
Project Start
2001-09-01
Project End
2006-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
4
Fiscal Year
2004
Total Cost
$253,531
Indirect Cost
Name
University of California Los Angeles
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Villalta, S Armando; Deng, Bo; Rinaldi, Chiara et al. (2011) IFN-? promotes muscle damage in the mdx mouse model of Duchenne muscular dystrophy by suppressing M2 macrophage activation and inhibiting muscle cell proliferation. J Immunol 187:5419-28
Tidball, James G (2011) Mechanisms of muscle injury, repair, and regeneration. Compr Physiol 1:2029-62
Tidball, James G; Villalta, S Armando (2010) Regulatory interactions between muscle and the immune system during muscle regeneration. Am J Physiol Regul Integr Comp Physiol 298:R1173-87
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Wehling-Henricks, Michelle; Sokolow, Sophie; Lee, Jamie J et al. (2008) Major basic protein-1 promotes fibrosis of dystrophic muscle and attenuates the cellular immune response in muscular dystrophy. Hum Mol Genet 17:2280-92
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Tidball, James G (2005) Mechanical signal transduction in skeletal muscle growth and adaptation. J Appl Physiol 98:1900-8
Nguyen, Hal X; Lusis, Aldons J; Tidball, James G (2005) Null mutation of myeloperoxidase in mice prevents mechanical activation of neutrophil lysis of muscle cell membranes in vitro and in vivo. J Physiol 565:403-13

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