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Skeletal muscle proteomic signature and metabolic impairment in pulmonary hypertension

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Abstract

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.

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Acknowledgments

The authors wish to thank the contribution of members of the Pulmonary Research Group team (www.pulmonaryarterialhypertension.ca) 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.

Funding

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.

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Authors and Affiliations

  1. Pulmonary Hypertension Research Group, Centre de Recherche de l’Institut de Cardiologie et de Pneumologie de Québec, Service de Pneumologie, 2725 Chemin Sainte-Foy, Québec City, QC, G1V 4G5, Canada

    Simon Malenfant, François Potus, Sandra Breuils-Bonnet, Aude Pflieger, Ève Tremblay, Sébastien Bonnet & Steeve Provencher

  2. Proteomics Center and Department of Molecular Medicine, CHUQ Research Center, Laval University, Quebec, QC, Canada

    Frédéric Fournier, Sylvie Bourassa, Benjamin Nehmé & Arnaud Droit

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  1. Simon Malenfant
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  2. François Potus
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  3. Frédéric Fournier
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  4. Sandra Breuils-Bonnet
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  5. Aude Pflieger
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  7. Ève Tremblay
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  8. Benjamin Nehmé
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  9. Arnaud Droit
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  10. Sébastien Bonnet
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  11. Steeve Provencher
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Corresponding authors

Correspondence to Sébastien Bonnet or Steeve Provencher.

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Simon Malenfant and François Potus contributed equally to this work.

Sébastien Bonnet and Steeve Provencher are co-senior authors.

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Malenfant, S., Potus, F., Fournier, F. et al. Skeletal muscle proteomic signature and metabolic impairment in pulmonary hypertension. J Mol Med 93, 573–584 (2015). https://doi.org/10.1007/s00109-014-1244-0

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