Impact of combined exercise training in peripheral and diaphragm muscles and in mortality in a preclinical model of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease characterised by systemic oxidative stress and inflammation that extends beyond the pulmonary vasculature to the musculoskeletal system. Combined exercise training (ET), incorporating aerobic and resistance components, is a promising non-pharmacological intervention, but its effects on musculoskeletal oxidative stress and inflammation remain unclear. To evaluate the effects of combined ET on musculoskeletal oxidative stress and inflammation, muscle wasting, and survival in a monocrotaline (MCT)-induced PAH. Male Wistar rats were assigned to MCT-treated sedentary (MCT-SED) or ET (MCT-ET) groups (n = 12/group), or saline-treated sedentary (SAL-SED) or ET (SAL-ET) controls (n = 8/group). PAH was induced via MCT injection (MCT, 40 mg/kg). The ET consisted of moderate-intensity interval aerobic (3x/week) and resistance (2x/week) training for four weeks. Muscle mass, oxidative stress and inflammation markers (IL-6, IL-10, TNF-α) were assessed in gastrocnemius and diaphragm muscles. PAH increased oxidative damage, reduced antioxidant defences, and elevated inflammatory markers in both muscles, contributing to muscle loss. Combined ET enhanced gastrocnemius antioxidant capacity (FRAP, SOD), reduced pro-oxidants (hydrogen peroxide, nitrite), and attenuated oxidative damage (TBARS, carbonyls) in both muscles. Combined ET decreased pro-inflammatory markers (IL-6, TNF-α), prevented diaphragm atrophy, and improved survival (MCT-SED vs. MCT-ET, p = 0.03; hazard ratio, 4.3; 95% CI, 1.2-15.1). Combined interval ET improved redox balance and inflammatory profiles in both peripheral and respiratory muscles. These adaptations were linked to reduced diaphragm muscle wasting and enhanced survival in MCT-induced PAH. Our findings support combined ET as a non-pharmacological strategy for managing systemic complications of PAH.