Effects of Physical Training on Mitochondrial Dynamic in Pulmonary Arterial Hypertension

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Abstract RATIONALE Pulmonary arterial hypertension (PAH) is a chronic progressive disease characterized by increased pulmonary vascular resistance and impaired exercise capacity. While rehabilitation programs have been shown to improve quality of life in PAH patients, the underlying mechanisms remain poorly understood. Exercise training is a powerful stimulus for mitochondrial biogenesis, enhancing mitochondrial quality and function which could lead to improved exercise capacity. However, exercise also generates reactive oxygen species (ROS) and reactive nitrogen species (RNS), which can cause damage to cellular components, including mitochondria, when present in excess. We hypothesize that mild exercise training in a murine model of PAH could modulate mitochondrial dynamics, particularly the balance between fusion and fission processes, by reducing ROS/RNS generation in the lungs and right ventricle. This modulation may contribute to the beneficial effects of exercise on mitochondrial health and overall disease progression in PAH. METHODS In a murine in vivo model of PAH induced by exposure to SU5416 and hypoxia, we simultaneously analyzed mitochondrial fusion proteins OPA-1 and MFN-2 and the fission protein DRP-1 in the lung, heart and muscle, as well as ROS/RNS generation. Half of the animals were subjected to a mild exercise program (45 minutes daily). Our study included four groups: two control groups (exercise (CE) n=6; and sedentary (CS) n=6) and two PAH groups (exercise (HE) n=6 and sedentary (HS) n=6). RESULTS We observed a decrease in the mitochondrial fusion protein OPA-1 in the HS and HE groups in the lung, heart and muscle, with significant results in the lung (p=0.028). The expression of MFN-2 was also decreased in the HS and HE groups in the heart and muscle, without significance. In contrast, DRP-1 was increased in the heart and muscle of the HS and HE groups with a significant decrease in the HE group compared to HS group (p=0.047). ROS generation was reduced in the HE group in both the lung (p=0.049) and muscle (p=0.033) when compared to the HS group. Notably, RNS generation in the muscle was low and nearly imperceptible in all studied groups. CONCLUSION Our results suggest that mild physical training in PAH reduces the expression of mitochondrial fusion and fission proteins correlating with a decrease in ROS/RNS generation. This aligns with the energetics demands of the cells and maintains mitochondrial homeostasis. Further studies are needed to fully understand the impact of physical training on mitochondrial dynamics in the context of PAH and confirm our findings.

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