Skeletal muscle proteomic signature in pulmonary arterial hypertension (1158.8)

Abstract

Introduction: Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular (RV) hypertrophy and ultimately failure. Numerous observations suggest that exercise limitation in pulmonary arterial hypertension (PAH) is not solely due to cardio‐pulmonary impairment, but that other determinants such as skeletal muscle abnormalities are involved. To better understand the exercise limitation origins in PAH, we studied the proteomic signature of skeletal muscle impairment in idiopathic PAH (iPAH) patients.Methods and results: Muscle proteins from 4 iPAH patients and 4 sex and age matched controls were extracted following quadriceps muscle biopsy. Fractioned peptides were then tagged using isobaric Tags for Relative and Absolute Quantitation (iTRAQ, ABsciex) specific for each patient. Tagged peptides were then mixed, fractioned, identified and quantified using mass spectrometry quantitative method. Over 900 proteins were identified, among them, 9 were under‐expressed and 7 were over‐expressed in all iPAH patient quadriceps. More than 75% of the under‐expressed proteins are involved in oxidative metabolism and most other highlighted proteins play a role in myogenesis. These findings were structurally associated with decreased mitochondrial density (citrate synthase assay) and impaired mitochondrial structure measured by electronic microscopy, while muscle fibers distribution was unchanged. Functionally, all these abnormalities resulted in decreases in oxidative metabolism (pyruvate dehydrogenases assay).Conclusions: For the first time in humans, we provide evidences that, as in lungs and the right ventricle, the impaired mitochondrial metabolism is also present in skeletal muscle suggesting that PAH might be considered as a global mitochondrial/metabolic disease.