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Abnormal Transition Pore Kinetics and Cytochrome C Release in Muscle Mitochondria of Patients with Chronic Obstructive Pulmonary Disease

¹ Servicio de Neumología, and ² Servicio de Cirugía de Tórax, ³ Unidad de Medicina y Cirugía Experimental, Hospital General Universitario Gregorio Marañón, Madrid, Spain; and ⁴ Servicio Neumologia, Hospital Universitario Son Dureta, Fundación Caubet-Cimera Illes Balears and CIBER Enfermedades Respiratorias (CIBERES), Mallorca, Spain

Correspondence and requests for reprints should be addressed to Luis Puente-Maestu, Servicio de Neumología, Hospital General Universitario Gregorio Marañón, c/Doctor Ezquerdo 46, 28007 Madrid, Spain. E-mail: lpuente{at}separ.es and lpuente.hgugm{at}salud.madrid.org

Skeletal muscle dysfunction (SMD) is frequent in patients with chronic obstructive pulmonary disease (COPD). Mitochondrial abnormalities appear to play a role in the pathogenesis of SMD. The mitochondrion permeability transition pore (MPTP) facilitates the leakage of mitochondrial matrix constituents, such as cytochrome c (cyto-c), and triggers apoptosis, known to occur in skeletal muscle of patients with COPD. Our objective was to study MPTP kinetics and cyto-c release in skeletal muscle mitochondria of patients with COPD. Mitochondria were isolated from the vastus lateralis (VL), external intercostalis (EI), and latissimus dorsi (LD) in 11 patients with COPD (66 ± 9 yr; FEV₁ 66 ± 13%) and 15 smokers with normal lung function (64 ± 6 yr; FEV₁ 95 ± 11%) who required thoracic surgery for a localized lung neoplasm. MPTP kinetics were determined spectrophotometrically (time to reach V'max, V'max and mitochondrial swelling) and cyto-c release by enzyme-linked immunosorbent assay. MPTP kinetics and cyto-c release were abnormal in patients with COPD in the three muscles studied. In addition, V'max of VL mitochondria was significantly related (P < 0.01) to BMI (r = –0.75 COPD, –0.67 control) and aerobic capacity (r = –0.70 COPD, –0.60 control) for the COPD group. MPTP kinetics and cyto-c release are abnormal in skeletal and respiratory muscles of patients with moderate COPD, suggesting a systemic mechanism(s) occurring early during the course of the disease.

CLINICAL RELEVANCE This controlled study describes, to our knowledge for the first time, abnormalities in the kinetics of the mitochondrial transition pore, a key structure in mitochondria-driven apoptosis and fiber biogenesis, and cytochrome-c release in skeletal muscle of patients with chronic obstructive pulmonary disease.