Journal of Molecular Medicine

, Volume 93, Issue 5, pp 573–584 | Cite as

Skeletal muscle proteomic signature and metabolic impairment in pulmonary hypertension

  • Simon Malenfant
  • François Potus
  • Frédéric Fournier
  • Sandra Breuils-Bonnet
  • Aude Pflieger
  • Sylvie Bourassa
  • Ève Tremblay
  • Benjamin Nehmé
  • Arnaud Droit
  • Sébastien Bonnet
  • Steeve Provencher
Original Article


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.

Key message

• 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.


Pulmonary hypertension Skeletal muscle Mitochondrial metabolism Proteomic Exercise capacity 



The authors wish to thank the contribution of members of the Pulmonary Research Group team ( as well as the work and contribution of the Respiratory Health Network tissue bank (IUCPQ site) for storing human quadriceps biopsies. The authors also acknowledged the help of Luce Bouffard, BSc, for her technical assistance with biopsies and Ryan Wong for technical assistance with the manuscript.

Conflict of interest

Dr. Bonnet is a consultant for Merck & Co, Inc. Dr. Provencher has received research grants from Actelion Pharmaceuticals Ltd, Bayer AG, and GlaxoSmithKline and has received speaker fees from Actelion Pharmaceuticals Ltd. The Pulmonary Hypertension Research Group is also supported by the Fond de Recherche du Québec en Santé (FRQ-S). The remaining authors reported no potential conflicts of interest.


S.M. is a recipient of a doctoral training award from the Fond de Recherche du Québec en Santé (FRQ-S), F.P. is a recipient of a doctoral training award from the Centre de Recherche de l’IUCPQ. S.B. holds grants from the Canadian Institute of Health Research (CIHR) and from the Heart and Stroke Foundation of Canada. He also holds a CIHR Research Chair on vascular biology. S.P. holds a CIHR grant and is a FRQ-S clinical scientist.

Supplementary material

109_2014_1244_MOESM1_ESM.pdf (556 kb)
ESM 1 (PDF 556 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Simon Malenfant
    • 1
  • François Potus
    • 1
  • Frédéric Fournier
    • 2
  • Sandra Breuils-Bonnet
    • 1
  • Aude Pflieger
    • 1
  • Sylvie Bourassa
    • 2
  • Ève Tremblay
    • 1
  • Benjamin Nehmé
    • 2
  • Arnaud Droit
    • 2
  • Sébastien Bonnet
    • 1
  • Steeve Provencher
    • 1
  1. 1.Pulmonary Hypertension Research GroupCentre de Recherche de l’Institut de Cardiologie et de Pneumologie de QuébecQuébec CityCanada
  2. 2.Proteomics Center and Department of Molecular Medicine, CHUQ Research CenterLaval UniversityQuebecCanada

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