Muscle weakness, injury and inflammation are important obstacles to normal function in individuals subjected to periods of muscle unloading followed by normal muscle use. These defects will acquire increased importance in health care for an aging population, in which convalescence can entail prolonged bedrest followed by attempts to regain normal ambulation. The design of preventative or therapeutic treatments to minimize muscle defects that arise upon reloading will rely upon identifying the factors that contribute to muscle injury, repair and growth. Our findings show that myeloid cells promote muscle injury and growth during reloading. We propose a model in which distinct populations of myeloid cells contribute to different phases of muscle adaptation to increased use. In our hypothesis, CD68+ macrophages target and remove cellular debris in advance of muscle repair and growth. These macrophages are classically-activated by Th1 cytokines, and then deactivated by interleukin-10 (IL-10). CD68+ cells are then replaced by two populations of alternatively-activated macrophages that promote muscle repair and growth. One population expresses the hemaglobin/haptoglobin receptor (CD163) and contributes to deactivation of the Th1 inflammatory response, and promotes muscle growth by the synthesis and release of leukemia inhibitory factor (LIF). The other population expresses the mannose receptor (CD206), participates in deactivating the Th1 response and promotes muscle healing. We will use mouse hindlimb suspension followed by reloading to induce muscle injury, repair and growth, and assess the effects of genetic modifications that perturb the expression of key molecules in our model. We will analyze the effects of the following manipulations on the repair and growth of muscle: 1) ablation of signaling by a cytokine necessary for classical activation of macrophages (IFN-gamma), 2) a macrophage-specific increase in expression of a cytokine that promotes growth (LIF), 3) null mutation of a cytokine necessary for deactivation of classically-activated macrophages (IL-10), and 4) a macrophage/neutrophil specific null mutation of a receptor that is necessary for alternative activation of macrophages (IL-4R alpha). This study will yield the first mechanistic findings concerning macrophage function in muscle repair and growth during increased loading.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR047855-09
Application #
7758317
Study Section
Special Emphasis Panel (ZRG1-MOSS-L (07))
Program Officer
Nuckolls, Glen H
Project Start
2001-09-01
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
9
Fiscal Year
2010
Total Cost
$321,233
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
Tidball, James G; Bertoni, Carmen (2014) Purloined mechanisms of bacterial immunity can cure muscular dystrophy. Cell Metab 20:927-9
Deng, Bo; Wehling-Henricks, Michelle; Villalta, S Armando et al. (2012) IL-10 triggers changes in macrophage phenotype that promote muscle growth and regeneration. J Immunol 189:3669-80
Villalta, S Armando; Deng, Bo; Rinaldi, Chiara et al. (2011) IFN-ýý 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
Villalta, S Armando; Nguyen, Hal X; Deng, Bo et al. (2009) Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy. Hum Mol Genet 18:482-96
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
Tidball, James G; Wehling-Henricks, Michelle (2007) Macrophages promote muscle membrane repair and muscle fibre growth and regeneration during modified muscle loading in mice in vivo. J Physiol 578:327-36
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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