Skeletal muscle proteomic signature and metabolic impairment in pulmonary hypertension
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- Malenfant, S., Potus, F., Fournier, F. et al. J Mol Med (2015) 93: 573. doi:10.1007/s00109-014-1244-0
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Exercise limitation comes from a close interaction between cardiovascular and skeletal muscle impairments. To better understand the implication of possible peripheral oxidative metabolism dysfunction, we studied the proteomic signature of skeletal muscle in pulmonary arterial hypertension (PAH). Eight idiopathic PAH patients and eight matched healthy sedentary subjects were evaluated for exercise capacity, skeletal muscle proteomic profile, metabolism, and mitochondrial function. Skeletal muscle proteins were extracted, and fractioned peptides were tagged using an iTRAQ protocol. Proteomic analyses have documented a total of 9 downregulated proteins in PAH skeletal muscles and 10 upregulated proteins compared to healthy subjects. Most of the downregulated proteins were related to mitochondrial structure and function. Focusing on skeletal muscle metabolism and mitochondrial health, PAH patients presented a decreased expression of oxidative enzymes (pyruvate dehydrogenase, p < 0.01) and an increased expression of glycolytic enzymes (lactate dehydrogenase activity, p < 0.05). These findings were supported by abnormal mitochondrial morphology on electronic microscopy, lower citrate synthase activity (p < 0.01) and lower expression of the transcription factor A of the mitochondria (p < 0.05), confirming a more glycolytic metabolism in PAH skeletal muscles. We provide evidences that impaired mitochondrial and metabolic functions found in the lungs and the right ventricle are also present in skeletal muscles of patients.
• Proteomic and metabolic analysis show abnormal oxidative metabolism in PAH skeletal muscle.
• EM of PAH patients reveals abnormal mitochondrial structure and distribution.
• Abnormal mitochondrial health and function contribute to exercise impairments of PAH.
• PAH may be considered a vascular affliction of heart and lungs with major impact on peripheral muscles.