Loss of quadriceps muscle oxidative phenotype and decreased endurance in patients with mild-to-moderate COPD.

Being well-established in advanced chronic obstructive pulmonary disease (COPD), skeletal muscle dysfunction and its underlying pathology have been scarcely investigated in patients with mild-to-moderate airflow obstruction. We hypothesized that a loss of oxidative phenotype (oxphen) associated with decreased endurance is present in the skeletal muscle of patients with mild-to-moderate COPD. In quadriceps muscle biopsies from 29 patients with COPD (forced expiratory volume in 1 s [FEV1] 58 +/- 16% pred, body mass index [BMI] 26 +/- 4 kg/m(2)) and 15 controls (BMI 25 +/- 3 kg/m(2)) we assessed fiber type distribution, fiber cross-sectional areas (CSA), oxidative and glycolytic gene expression, OXPHOS protein levels, metabolic enzyme activity, and levels of oxidative stress markers. Quadriceps function was assessed by isokinetic dynamometry, body composition by dual-energy X-ray absorptiometry, exercise capacity by an incremental load test, and physical activity level by accelerometry. Compared with controls, patients had comparable fat-free mass index, quadriceps strength, and fiber CSA, but quadriceps endurance was decreased by 29% (P = 0.002). Patients with COPD had a clear loss of muscle oxphen: a fiber type I-to-II shift, decreased levels of OXPHOS complexes IV and V subunits (47% and 31%, respectively; P <0.05), a decreased ratio of 3-hydroxyacyl-CoA dehydrogenase/phosphofructokinase (PFK) enzyme activities (38%, P <0.05), and decreased peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (40%; P <0.001) vs. increased PFK (67%; P <0.001) gene expression levels. Within the patient group, markers of oxphen were significantly positively correlated with quadriceps endurance and inversely with the increase in plasma lactate relative to work rate during the incremental test. Levels of protein carbonylation, tyrosine nitration, and malondialdehyde protein adducts were comparable between patients and controls. However, among patients, oxidative stress levels were significantly inversely correlated with markers of oxphen and quadriceps endurance. Reduced muscle endurance associated with underlying loss of muscle oxphen is already present in patients with mild-to-moderate COPD without muscle wasting.