Skeletal muscle proteomic signature and metabolic impairment in pulmonary hypertension
- 726 Downloads
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.
KeywordsPulmonary hypertension Skeletal muscle Mitochondrial metabolism Proteomic Exercise capacity
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.
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.
- 6.Potus F, Malenfant S, Graydon C, Mainguy V, Tremblay E, Breuils-Bonnet S, Ribeiro F, Porlier A, Maltais F, Bonnet S et al (2014) Impaired angiogenesis and peripheral muscle microcirculation loss contribute to exercise intolerance in pulmonary arterial hypertension. Am J Respir Crit Care Med 190:318–328PubMedGoogle Scholar
- 10.Paulin R, Dromparis P, Sutendra G, Gurtu V, Zervopoulos S, Bowers L, Haromy A, Webster L, Provencher S, Bonnet S et al (2014) Sirtuin 3 deficiency is associated with inhibited mitochondrial function and pulmonary arterial hypertension in rodents and humans. Cell Metab 20:827–839CrossRefPubMedGoogle Scholar
- 11.Piao L, Fang Y-H, Cadete VJJ, Wietholt C, Urboniene D, Toth PT, Marsboom G, Zhang HJ, Haber I, Rehman J et al (2010) The inhibition of pyruvate dehydrogenase kinase improves impaired cardiac function and electrical remodeling in two models of right ventricular hypertrophy: resuscitating the hibernating right ventricle. J Mol Med 88:47–60CrossRefPubMedCentralPubMedGoogle Scholar
- 12.Sutendra G, Dromparis P, Paulin R, Zervopoulos S, Haromy A, Nagendran J, Michelakis ED (2013) A metabolic remodeling in right ventricular hypertrophy is associated with decreased angiogenesis and a transition from a compensated to a decompensated state in pulmonary hypertension. J Mol Med 91:1315–1327CrossRefPubMedGoogle Scholar
- 19.Bonnet S, Michelakis ED, Porter C, Andrade-Navarro M, Thebaud B, Breuils-Bonnet S, Haromy A, Harry G, Moudgil R, McMurtry S et al (2006) An abnormal mitochondrial-hypoxia inducible factor-1 alpha-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats—similarities to human pulmonary arterial hypertension. Circulation 113:2630–2641CrossRefPubMedGoogle Scholar
- 23.Marsboom G, Wietholt C, Haney CR, Toth PT, Ryan JJ, Morrow E, Thenappan T, Bache-Wiig P, Piao L, Paul J et al (2012) Lung 18 F-fluorodeoxyglucose positron emission tomography for diagnosis and monitoring of pulmonary arterial hypertension. Am J Respir Crit Care Med 185:670–679CrossRefPubMedCentralPubMedGoogle Scholar
- 31.Tomasetti M, Nocchi L, Staffolani S, Manzella N, Amati M, Goodwin J, Kluckova K, Nguyen M, Strafella E, Bajzikova M et al (2014) MicroRNA-126 suppresses mesothelioma malignancy by targeting IRS1 and interfering with the mitochondrial function. Antioxid Redox Signal 21:2109–2125CrossRefPubMedGoogle Scholar
- 40.Hansmann G, Wagner RA, Schellong S, Perez VAJ, Urashima T, Wang L, Sheikh AY, Suen RS, Stewart DJ, Rabinovitch M (2007) Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-gamma activation. Circulation 115:1275–1284PubMedGoogle Scholar
- 43.Aguer C, Mercier J, Man CYW, Metz L, Bordenave S, Lambert K, Jean E, Lantier L, Bounoua L, Brun JF et al (2010) Intramyocellular lipid accumulation is associated with permanent relocation ex vivo and in vitro of fatty acid translocase (FAT)/CD36 in obese patients. Diabetologia 53:1151–1163CrossRefPubMedGoogle Scholar
- 50.Maltais F, Decramer M, Casaburi R, Barreiro E, Burelle Y, Debigaré R, Dekhuijzen PNR, Franssen F, Gayan-Ramirez G, Gea J et al (2014) An official american thoracic society/european respiratory society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 189:e15–e62CrossRefPubMedCentralPubMedGoogle Scholar