Impaired exercise capacity and skeletal muscle function in a mouse model of pulmonary inflammation

Pulmonary TNF alpha 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 alpha impairs cardiac and skeletal muscle function, and both contribute to exercise limitation. Using a surfactant protein C promoter-TNF alpha construct, TNF alpha was overexpressed throughout life in mouse lungs (SP-C/TNF alpha+). TNF alpha levels in wild-type (WT) female serum and lung were two- and threefold higher than in WT male mice. In SP-C/TNF alpha+ mice, TNF alpha increased similarly in both sexes. Treadmill exercise was impaired only in male SP-C/TNF alpha+ mice. While increases in lung volume and airspace size induced by TNF alpha 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 alpha overexpression. Fatigue measured in isolated soleus and EDL was more rapid only in soleus of male SP-C/TNF alpha+ mice and accompanied by a loss of oxidative IIa fibers, citrate synthase activity, and PGC-1 alpha 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 alpha+ mice. These data indicate that male, but not female, mice overexpressing pulmonary TNF alpha 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.