Skeletal Muscle Mitochondrial Abnormalities and the Metabolic Syndrome in PAH

NCT03979482 | Completed

• 1 other identifier: Syndrome métabolique IRM
• Study Type: observational
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Pulmonary arterial hypertension (PAH) is characterized by the progressive increase in pulmonary vascular resistance ultimately leading to right ventricular (RV) failure. Its prevalence is estimated at 40-60 persons per million and predominantly affects people between 20 and 60 years of age. Newly available therapies have improved the 3-year survival to \>80%. This improvement in prognosis brings new challenges for clinicians: PAH has changed from a rapidly fatal disease to a chronic disorder with persistent exercise limitation and poor quality of life. Many observations suggest that exercise limitation in PAH is not simply due to pulmonary hemodynamic impairment, but that other determinants are involved. Interestingly, even in absence of obesity or diabetes, insulin resistance (IR) and metabolic syndrome (MS) are highly prevalent amongst PAH patients and associated with worse outcomes. Indeed, lipid accumulation in skeletal muscle (a feature of IR) is observed in both human and experimental model of PAH, but its impact on skeletal muscle function and thus exercise intolerance in PAH remains elusive. Over the past years, several pathophysiological pathways activated by MS have been identified, including the downregulation PPARg/PGC1a and the insulin signalling pathways, especially the insulin-receptor substrate 1 (IRS1)-mediated one. The decrease in these axes is associated with lipid accumulation and impaired mitochondrial function. The investigators previously reported in PAH lungs that the downregulation of these pathways contributes to the establishment of the Warburg effect. This metabolic unbalance contributes to pulmonary artery smooth muscle (PASMC) proliferation, and resistance to apoptosis contributing to PA remodelling. The investigators recently documented that PAH skeletal muscles are less perfused and are also characterized by the presence of a Warburg effect. These features were independent of daily life physical activity. Nonetheless, the origin of these abnormalities and their impact on skeletal muscle function have never been studied. The investigators propose to determine whether or not MS seen in PAH patients impairs mitochondrial functions through an IRS1/PPARg/PGC1-dependent mechanism, which will ultimately decrease skeletal muscle function and perfusion, and thus overall exercise capacity.

Conditions

Pulmonary Artery Hypertension

Keywords

skeletal muscle mitochondrial abnormalities; metabolic syndrome; insulin resistance

Outcome Measures

Primary Outcomes (5)

• Concentration of Intramuscular lipid

  MR imaging will be used to assess fat infiltration within the quadriceps muscle, liver and heart.

  Through study completion, an average of 1 year

• Level of physical activity

  Subjects' daily life physical activities quantified using a physical activity monitor (SenseWear® armband).

  During 1 week

• Level of mitochondrial activity in PAH skeletal muscles

  The expression of several key transcriptional factors and coregulators that are known to regulate mitochondrial biogenesis will be examined, including PPARγ coactivator 1α (PGC-1α), NRF-2, and mitochondrial transcription factor A (WB and immunoprecipitation assay). Mitochondrial oxidative (citrate synthase, hexokinase) and glycolytic (lactate dehydrogenase, phosphofructokinase) enzymes activity (spectrophotometric techniques) will also be assessed.

  Through study completion, an average of 1 year

• Change in serine residues (Ser307, Ser312, Ser616, Ser636) due to IRS-1 serine phosphorylation

  Differences in phosphorylation of IRS-1 on critical serine residues (Ser307, Ser312, Ser616, Ser636) that have been implicated to interfere with insulin signaling in vitro will be assessed on skeletal muscle biopsies by Western Blot.

  Through study completion, an average of 1 year

• Level of PKCθ activation/activity

  Will be assessed on skeletal muscle biopsies using isoform-specific PKC antibodies (WB) and a PKC enzyme assay kit.

  Through study completion, an average of 1 year

Study Arms (2)

PAH patients

Male and female subjects, aged between 20 and 60 years old. Absence of obesity/diabètes. PAH patients presenting with metabolic syndrome (MS).

Sedentary healthy patients

Male and female subjects, aged between 20 and 60 years old. Absence of obesity/diabètes. Healthy but sedentary subjects.

Eligibility Criteria

• Age: 20 Years - 60 Years
• Sex: all
• Age Groups: Adult (18-64)
• Sampling Method: Non-Probability Sample

Study Population

The proposed experiments will be performed on PAH patients (n=10-20) vs. 10 healthy but sedentary subjects matched for age, gender, height and weight (definition based on current recommendations), excluding patients with clinically relevant conditions (e.g. diabetes). These individuals are continuously identified through our systematic plasma biobanking process at the time of right heart catheterization (CER#20735), in which roughly 40% of PAH patients with no obesity/diabetes have MS.

You may qualify if:

• PAH patients: Male and female subjects, patients presenting with metabolic syndrome (MS).
• Sedentary healthy patients: Male and female subjects. Healthy but sedentary subjects.

You may not qualify if:

• Presence of obesity/diabetes

Sponsors & Collaborators

• Laval University: lead

Study Sites (1)

IUCPQ-UL

Québec, Quebec, G1V 4G5, Canada

Location

Related Publications (12)

• Pugh ME, Robbins IM, Rice TW, West J, Newman JH, Hemnes AR. Unrecognized glucose intolerance is common in pulmonary arterial hypertension. J Heart Lung Transplant. 2011 Aug;30(8):904-11. doi: 10.1016/j.healun.2011.02.016. Epub 2011 Apr 13.

  PMID: 21493097 BACKGROUND

• Hansmann G, Wagner RA, Schellong S, Perez VA, Urashima T, Wang L, Sheikh AY, Suen RS, Stewart DJ, Rabinovitch M. Pulmonary arterial hypertension is linked to insulin resistance and reversed by peroxisome proliferator-activated receptor-gamma activation. Circulation. 2007 Mar 13;115(10):1275-84. doi: 10.1161/CIRCULATIONAHA.106.663120. Epub 2007 Mar 5.

  PMID: 17339547 BACKGROUND

• Malenfant S, Potus F, Fournier F, Breuils-Bonnet S, Pflieger A, Bourassa S, Tremblay E, Nehme B, Droit A, Bonnet S, Provencher S. Skeletal muscle proteomic signature and metabolic impairment in pulmonary hypertension. J Mol Med (Berl). 2015 May;93(5):573-84. doi: 10.1007/s00109-014-1244-0. Epub 2014 Dec 30.

  PMID: 25548805 BACKGROUND

• Paulin R, Michelakis ED. The metabolic theory of pulmonary arterial hypertension. Circ Res. 2014 Jun 20;115(1):148-64. doi: 10.1161/CIRCRESAHA.115.301130.

  PMID: 24951764 BACKGROUND

• Samuel VT, Petersen KF, Shulman GI. Lipid-induced insulin resistance: unravelling the mechanism. Lancet. 2010 Jun 26;375(9733):2267-77. doi: 10.1016/S0140-6736(10)60408-4.

  PMID: 20609972 BACKGROUND

• Morino K, Petersen KF, Dufour S, Befroy D, Frattini J, Shatzkes N, Neschen S, White MF, Bilz S, Sono S, Pypaert M, Shulman GI. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest. 2005 Dec;115(12):3587-93. doi: 10.1172/JCI25151. Epub 2005 Nov 10.

  PMID: 16284649 BACKGROUND

• Potus F, Malenfant S, Graydon C, Mainguy V, Tremblay E, Breuils-Bonnet S, Ribeiro F, Porlier A, Maltais F, Bonnet S, Provencher S. Impaired angiogenesis and peripheral muscle microcirculation loss contribute to exercise intolerance in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2014 Aug 1;190(3):318-28. doi: 10.1164/rccm.201402-0383OC.

  PMID: 24977625 BACKGROUND

• Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstrale M, Laurila E, Houstis N, Daly MJ, Patterson N, Mesirov JP, Golub TR, Tamayo P, Spiegelman B, Lander ES, Hirschhorn JN, Altshuler D, Groop LC. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003 Jul;34(3):267-73. doi: 10.1038/ng1180.

  PMID: 12808457 BACKGROUND

• Griffin ME, Marcucci MJ, Cline GW, Bell K, Barucci N, Lee D, Goodyear LJ, Kraegen EW, White MF, Shulman GI. Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes. 1999 Jun;48(6):1270-4. doi: 10.2337/diabetes.48.6.1270.

  PMID: 10342815 BACKGROUND

• Yu C, Chen Y, Cline GW, Zhang D, Zong H, Wang Y, Bergeron R, Kim JK, Cushman SW, Cooney GJ, Atcheson B, White MF, Kraegen EW, Shulman GI. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem. 2002 Dec 27;277(52):50230-6. doi: 10.1074/jbc.M200958200. Epub 2002 Nov 14.

  PMID: 12006582 BACKGROUND

• Holmstrom KM, Baird L, Zhang Y, Hargreaves I, Chalasani A, Land JM, Stanyer L, Yamamoto M, Dinkova-Kostova AT, Abramov AY. Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration. Biol Open. 2013 Jun 20;2(8):761-70. doi: 10.1242/bio.20134853. eCollection 2013 Aug 15.

  PMID: 23951401 BACKGROUND

• Liu Z, Dou W, Ni Z, Wen Q, Zhang R, Qin M, Wang X, Tang H, Cao Y, Wang J, Zhao S. Deletion of Nrf2 leads to hepatic insulin resistance via the activation of NF-kappaB in mice fed a high-fat diet. Mol Med Rep. 2016 Aug;14(2):1323-31. doi: 10.3892/mmr.2016.5393. Epub 2016 Jun 10.

  PMID: 27315552 BACKGROUND

MeSH Terms

Conditions

Familial Primary Pulmonary Hypertension; Metabolic Syndrome; Insulin Resistance

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• Steeve Provencher, MD, MSc

  IUCPQ - Université Laval

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: May 24, 2019
• First Posted: June 7, 2019
• Study Start: June 1, 2019
• Primary Completion: April 15, 2023
• Study Completion: April 15, 2023
• Last Updated: April 18, 2023

Record last verified: 2023-04

Locations

CA (1)