Signaling pathways underlying skeletal muscle wasting in experimental pulmonary arterial hypertension

Abstract

BackgroundSkeletal muscle wasting contributes to the poor functional status and quality of life of patients with pulmonary arterial hypertension (PAH). The present study aims to characterize the molecular mechanism underlying skeletal muscle wasting in experimental PAH induced by monocrotaline (MCT). MethodsMale Wistar rats were randomly injected with saline solution (CONT; n=10) or MCT (MCT; 60mg/kg, s.c.; n=15). After 4weeks of MCT or vehicle administration, animals were anesthetized and submitted to right ventricular (RV) hemodynamic evaluation. Blood and gastrocnemius samples were collected and stored for analysis. ResultsMCT group developed PAH (70% increase in RV peak systolic pressure) RV dysfunction (increased end-diastolic pressure and Tau), and body and muscle wasting (reduction of 20%, 16% and 30% on body weight, gastrocnemius mass and fiber cross sectional area, respectively). Muscle atrophy was associated with a decrease in type I MHC. Circulating (C reactive protein, myostatin and IL-1beta) and local catabolic markers (MAFbx/atrogin-1, protease activity) were increased in MCT animals, while Akt/mTOR pathway was preserved. Mitochondria isolated from gastrocnemius of MCT animals showed decreased activity of ATP synthase, lower levels of Tfam, accumulation of oxidatively modified proteins together with reduced levels of paraplegin. ConclusionsOur data suggests an anabolic/catabolic imbalance in gastrocnemius from MCT-induced PAH rats. Accumulation of dysfunctional mitochondria due to the inefficiency of protein quality control systems to eliminate damaged proteins could also contribute to muscle atrophy in PAH.