Reduced Exercise Capacity Occurs Before Intrinsic Changes In Skeletal Muscle In Experimental Rat Models Of Pulmonary Hypertension

Background: Pulmonary Hypertension (PH) is defined with mean pulmonary arterial pressure greater than 20 mmHg at rest. Reduced exercise capacity in PH significantly impacts quality of life. While the cause of reduced exercise capacity in PH remains unclear, it is suggested that regional skeletal muscle adaptions may play a role. The objective of this study was to investigate whether intrinsic changes in skeletal muscle determine exercise capacity in PH using preclinical PH rat models with different PH severity. Methods and Results: PH was induced in adult Sprague-Dawley (SD) or Fischer (CDF) rats with one dose of SU5416 (20 mg/kg) injection, followed by 3 weeks of hypoxia and additional 1-4 weeks of normoxia exposure. Rats injected with vehicle and housed in normoxia were used as controls. Echocardiography and hemodynamics were performed to assess PH and cardiac function. Exercise capacity was assessed by VO 2 max. Skeletal muscle structural changes (atrophy, fiber type switch, and capillary density), mitochondrial function, isometric force, and fatigue profile were assessed in soleus muscles. In SD rats, right ventricular systolic dysfunction is associated with reduced exercise capacity in PH rats at 7 weeks timepoint in comparison to control rats, while no changes were observed in skeletal muscle structure, mitochondrial function, isometric force, or fatigue profile. CDF rats at 4 weeks timepoint developed a more severe PH and, in addition to right ventricular dysfunction, the reduced exercise capacity in these rats is associated with skeletal muscle atrophy; however, mitochondrial function, isometric force, and fatigue profile in skeletal muscle remain unchanged. Conclusions: Our study demonstrated that reduced exercise capacity in PH occurs before intrinsic changes in skeletal muscle, suggesting that alterations in skeletal muscle are not causative to exercise intolerance in PH, while they may worsen exercise capacity collaboratively with primary factors in the late stage of PH. In addition, our study supports the notion that improving central cardiopulmonary impairments at the early stage of PH may be critical in preventing or delaying the occurrence of exercise limitation in settings of PH.