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Loss of IL-15 receptor ? alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles.

ABSTRACT: IL-15 receptor ? (IL-15R?) is a component of the heterotrimeric plasma membrane receptor for the pleiotropic cytokine IL-15. However, IL-15R? is not merely an IL-15 receptor subunit, as mice lacking either IL-15 or IL-15R? have unique phenotypes. IL-15 and IL-15R? have been implicated in muscle phenotypes, but a role in muscle physiology has not been defined. Here, we have shown that loss of IL-15R? induces a functional oxidative shift in fast muscles, substantially increasing fatigue resistance and exercise capacity. IL-15R?-knockout (IL-15R?-KO) mice ran greater distances and had greater ambulatory activity than controls. Fast muscles displayed fatigue resistance and a slower contractile phenotype. The molecular signature of these muscles included altered markers of mitochondrial biogenesis and calcium homeostasis. Morphologically, fast muscles had a greater number of muscle fibers, smaller fiber areas, and a greater ratio of nuclei to fiber area. The alterations of physiological properties and increased resistance to fatigue in fast muscles are consistent with a shift toward a slower, more oxidative phenotype. Consistent with a conserved functional role in humans, a genetic association was found between a SNP in the IL15RA gene and endurance in athletes stratified by sport. Therefore, we propose that IL-15R? has a role in defining the phenotype of fast skeletal muscles in vivo.

SUBMITTER: Pistilli EE

PROVIDER: S-EPMC3148729 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Loss of IL-15 receptor α alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles.

Pistilli Emidio E EE Bogdanovich Sasha S Garton Fleur F Yang Nan N Gulbin Jason P JP Conner Jennifer D JD Anderson Barbara G BG Quinn LeBris S LS North Kathryn K Ahima Rexford S RS Khurana Tejvir S TS

The Journal of clinical investigation 20110718 8

IL-15 receptor α (IL-15Rα) is a component of the heterotrimeric plasma membrane receptor for the pleiotropic cytokine IL-15. However, IL-15Rα is not merely an IL-15 receptor subunit, as mice lacking either IL-15 or IL-15Rα have unique phenotypes. IL-15 and IL-15Rα have been implicated in muscle phenotypes, but a role in muscle physiology has not been defined. Here, we have shown that loss of IL-15Rα induces a functional oxidative shift in fast muscles, substantially increasing fatigue resistance ...[more]

PMID: 21765213

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Project description:Patients with chronic obstructive pulmonary disease (COPD) usually develop skeletal muscle dysfunction, which represents a major comorbidity in these patients and is strongly associated with mortality and other poor outcomes. Although clinical data indicates that accelerated protein degradation and metabolic disruption are common associations of muscle dysfunction in COPD, there is very limited data on the mechanisms regulating the process, in part, due to the lack of research performed on a validated animal model of pulmonary emphysema. This model deficiency complicates the translational value of data generated with highly reductionist settings. Here, we use an established transgenic animal model of COPD based on inducible IL-13-driven pulmonary emphysema (IL-13TG) to interrogate the mechanisms of skeletal muscle dysfunction. Skeletal muscles from these emphysematous mice develop most features present in COPD patients, including atrophy, decreased oxygen consumption, and reduced force-generation capacity. Analysis of muscle proteome indicates downregulation of succinate dehydrogenase C (SDH-C), which correlates with reduced enzymatic activity, also consistent with previous clinical observations. Ontology terms identified with human data, such as ATP binding/bioenergetics are also downregulated in this animal's skeletal muscles. Moreover, chronic exercise can partially restore muscle mass, metabolic and force-generation capacity, and SDH activity in COPD mice. We conclude that this animal model of COPD/emphysema is an adequate platform to further investigate mechanisms of muscle dysfunction in this setting and demonstrates multiple approaches that can be used to address specific mechanisms regulating this process.NEW & NOTEWORTHY Skeletal muscle dysfunction is a relevant comorbidity in patients with chronic obstructive pulmonary disease (COPD). Mechanistic research in the area has so far been accomplished with models based on specific exposures to otherwise healthy animals, and no investigation using an established and validated animal model of COPD has been accomplished. We present an animal model of COPD that was previously shown to recapitulate pulmonary functional and histologic features present in patients with COPD, and demonstrates most of the features present in patients with pulmonary emphysema-associated muscle dysfunction, which we proposed as an adequate tool to develop mechanistic research in the area.

Dataset Information

Loss of IL-15 receptor ? alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles.

Publications

Loss of IL-15 receptor α alters the endurance, fatigability, and metabolic characteristics of mouse fast skeletal muscles.

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