Impaired exercise capacity and skeletal muscle function in a mouse model of pulmonary inflammation
Impaired exercise capacity and skeletal muscle function in a mouse model of pulmonary inflammation
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DOI：
10.1152/japplphysiol.00607.2012
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发表时间：
2013-05-01
影响因子：
3.3
通讯作者：
Breen, Ellen C.
中科院分区：
文献类型：
--
作者：
Tang, Kechun;Murano, George;Breen, Ellen C.
在部分中重度慢性阻塞性肺疾病(COPD)患者中，肺肿瘤坏死因子α与运动能力下降有关。我们假设，长时间高表达肺肿瘤坏死因子α会损害心肌和骨骼肌功能，两者都会导致运动受限。利用表面活性蛋白C启动子-肿瘤坏死因子α的构建，肿瘤坏死因子α在小鼠肺中终生过表达(SP-C/肿瘤坏死因子α+)。野生型(WT)雌性小鼠血清和肺组织中的肿瘤坏死因子α水平分别是WT雄性小鼠的两倍和三倍。在SP-C/肿瘤坏死因子α+小鼠中，肿瘤坏死因子α在两性中的升高程度相似。跑台运动仅在雄性SP-C/肿瘤坏死因子α+小鼠中受损。虽然由肿瘤坏死因子α引起的肺体积和肺泡大小的增加在两性中是相似的，但只有雄性小鼠才能明显地看到肺动脉高压以及下体和肌肉质量。左心功能(心输出量、每搏输出量、左心室最大压力、左心室最大压力dp/dt)不受肿瘤坏死因子α过表达的影响。在分离的比目鱼肌和EDL中，仅在雄性SP-C/TNFα+小鼠的比目鱼肌中测量到的疲劳更快，并伴有氧化IIa纤维、柠檬酸合成酶活性和PGC-1αmRNA的丢失，而阿托金-1和MuRF1的表达也仅在雄性小鼠中增加。在雌性和雄性SP-C/TNFα+小鼠中，反映氧可获得性和收缩能力的原位腓肠肌疲劳性同样降低。这些数据表明，过度表达肺肿瘤坏死因子α的雄性小鼠(而不是雌性小鼠)容易受到运动限制，这可能是由于肌肉萎缩和氧化肌肉表型的丧失，雌性小鼠的保护可能是由于雌激素。
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.