HIGHLIGHTED TOPIC Muscle Dysfunction in COPD Impaired exercise capacity and skeletal muscle function in a mouse model of pulmonary inflammation

Tang K, Murano G, Wagner H, Nogueira L, Wagner PD, Tang A, Dalton ND, Gu Y, Peterson KL, Breen EC. Impaired exercise capacity and skeletal muscle function in a mouse model of pulmonary inflammation. J Appl Physiol 114: 1340–1350, 2013. First published February 28, 2013; doi:10.1152/japplphysiol.00607.2012.—Pulmonary TNF has been linked to reduced exercise capacity in a subset of patients with moderate to severe chronic obstructive pulmonary disease (COPD). We hypothesized that prolonged, high expression of pulmonary TNF impairs cardiac and skeletal muscle function, and both contribute to exercise limitation. Using a surfactant protein C promoter-TNF construct, TNF was overexpressed throughout life in mouse lungs (SP-C/TNF ). TNF levels in wild-type (WT) female serum and lung were twoand threefold higher than in WT male mice. In SP-C/TNF mice, TNF increased similarly in both sexes. Treadmill exercise was impaired only in male SP-C/TNF mice. While increases in lung volume and airspace size induced by TNF were comparable in both sexes, pulmonary hypertension along with lower body and muscle mass were evident only in male mice. Left ventricular (LV) function (cardiac output, stroke volume, LV maximal pressure, and LV maximal pressure dP/dt) was not altered by TNF overexpression. Fatigue measured in isolated soleus and EDL was more rapid only in soleus of male SP-C/TNF mice and accompanied by a loss of oxidative IIa fibers, citrate synthase activity, and PGC-1 mRNA and increase in atrogin-1 and MuRF1 expression also only in male mice. In situ gastrocnemius fatigue resistance, reflecting both oxygen availability and contractility, was decreased similarly in female and male SP-C/TNF mice. These data indicate that male, but not female, mice overexpressing pulmonary TNF are susceptible to exercise limitation, possibly due to muscle wasting and loss of the oxidative muscle phenotype, with protection in females possibly due to estrogen.