Author(s): ZUCCARELLI, L., BROCCA, L., ZAMBONI, F., BALDASSARRE, G., GASPARINI, A., BOCHICCHIO, G., PATRUNO, V., BOTTINELLI, R., CAPELLI, C., TAM, E., CRISAFULLI, E., PELLEGRINO, M.A., GRASSI, B., Institution: UNIVERSITY OF UDINE , Country: ITALY, Abstract-ID: 1019

INTRODUCTION:
Exercise intolerance is a hallmark of chronic obstructive pulmonary disease (COPD) and is only partially explained by respiratory limitations. Skeletal muscle dysfunction, comprehending mitochondrial impairment, may represent a key determinant of reduced functional capacity. However, the contribution of mitochondrial dysfunction in skeletal muscles to exercise intolerance in COPD remains insufficiently characterized.
METHODS:
Fourteen COPD patients (7 females and 7 males; age 67±8 years and body mass 70±17 kg) with moderate-to-severe airflow obstruction (forced expiratory volume in one second, FEV1= 50.4±7.9 %predicted) and 31 healthy controls (CTRL) were recruited; 7 participants per group underwent vastus lateralis muscle biopsy. Exercise tolerance was assessed by cardiopulmonary exercise testing performed on a cycle ergometer to determine peak pulmonary oxygen uptake (V̇O2peak). Skeletal muscle oxidative metabolism was evaluated ex vivo using high-resolution respirometry (HRR) in permeabilized skeletal muscle fibers. Leak respiration (LEAK), maximal ADP-stimulated mitochondrial respiration (OXPHOS) and ADP sensitivity (apparent Km) were assessed in duplicate in experimental conditions of unlimited O2 availability. Markers of mitochondrial content were assessed, including citrate synthase (CS) expression and activity, skeletal muscle fiber-type composition (myosin heavy chain isoforms) and capillary density were determined.
RESULTS:
V̇O2peak was markedly reduced in COPD compared to CTRL (16.4±3.0 vs. 29.9±5.7 ml·kg⁻¹·min⁻¹; p< 0.05). Ex vivo mitochondrial respiration assessed by HRR showed no differences between groups. In COPD, LEAK (12±4 pmol·s⁻¹·mg⁻¹) and OXPHOS (41±13 pmol·s⁻¹·mg⁻¹) respirations were similar to the values in CTRL (14±4 and 40±14, respectively; p>0.05). Apparent ADP sensitivity tended to be higher (lower apparent Km) in COPD compared to CTRL (+28%; p=0.15). Markers of mitochondrial content (CS) were not different between groups (p>0.05). In contrast, COPD patients exhibited a higher proportion of type IIa muscle fibers (Δ=+25%; p< 0.01) and a reduced capillary density (-25%; p=0.01) vs. CTRL.
CONCLUSION:
COPD patients exhibited markedly reduced exercise tolerance despite preserved mitochondrial mass and respiratory capacity, as evidenced by preserved CS expression and activity and preserved mitochondrial respiration. These findings suggest that exercise intolerance in COPD is unlikely to be driven by mitochondrial respiratory dysfunction, but rather by altered muscle O2 delivery, including changes in fiber-type composition and reduced capillary density. Importantly, because intrinsic mitochondrial function seems to be preserved, interventions aimed at improving “upstream” determinants of O2 delivery -such as respiratory, cardiovascular and microvascular functions, muscle perfusion, capillarization, peripheral O2 diffusion - may effectively enhance exercise tolerance in COPD patients.
Funding: MUR PRIN Project 2022, P2022XX7YL.