title: Impaired exercise capacity and skeletal muscle function in a mouse model of pulmonary inflammation.
abstract: Pulmonary TNFα 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 TNFα impairs cardiac and skeletal muscle function, and both contribute to exercise limitation. Using a surfactant protein C promoter-TNFα construct, TNFα was overexpressed throughout life in mouse lungs (SP-C/TNFα+). TNFα levels in wild-type (WT) female serum and lung were two- and threefold higher than in WT male mice. In SP-C/TNFα+ mice, TNFα increased similarly in both sexes. Treadmill exercise was impaired only in male SP-C/TNFα+ mice. While increases in lung volume and airspace size induced by TNFα 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 TNFα overexpression. Fatigue measured in isolated soleus and EDL was more rapid only in soleus of male SP-C/TNFα+ mice and accompanied by a loss of oxidative IIa fibers, citrate synthase activity, and PGC-1α 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/TNFα+ mice. These data indicate that male, but not female, mice overexpressing pulmonary TNFα 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.
authors: Department of Medicine, University of California, San Diego, La Jolla, California 92093-0623, USA.
authors: Kechun
authors: K
authors: Tang
authors: George
authors: G
authors: Murano
authors: Harrieth
authors: H
authors: Wagner
authors: Leonardo
authors: L
authors: Nogueira
authors: Peter D
authors: PD
authors: Wagner
authors: Alisa
authors: A
authors: Tang
authors: Nancy D
authors: ND
authors: Dalton
authors: Yusu
authors: Y
authors: Gu
authors: Kirk L
authors: KL
authors: Peterson
authors: Ellen C
authors: EC
authors: Breen
mesh_terms: D042682:Angiopoietins / Q000502:physiology; D000818:Animals; D001835:Body Weight; D004195:Disease Models, Animal; D004967:Estrogens / Q000502:physiology; D005260:Female; D015870:Gene Expression; D006321:Heart / Q000503:physiopathology; D036341:Intercellular Signaling Peptides and Proteins; D008168:Lung / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology*; D010455:Peptides / Q000235:genetics; D005082:Physical Exertion; D011401:Promoter Regions, Genetic; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D037721:Pulmonary Surfactant-Associated Protein C; D012727:Sex Characteristics; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics / Q000502:physiology
chemical_list: D042682:Angiopoietins; D004967:Estrogens; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D037721:Pulmonary Surfactant-Associated Protein C; C489680:Sftpc protein, mouse; D014409:Tumor Necrosis Factor-alpha
keywords: PGC-1; angiopoietin; atrophy; chronic obstructive pulmonary disease; fatigue