Summary of studies analysing muscle function in pulmonary hypertension
| First author, year, [ref.] | Type of muscle | Sample size n | Patients | Animal model | Muscle function | Cellular changes |
| Vescovo, 1998 [56] | Peripheral (M. soleus + EDL) | 30 16/14# | MCT30 | ↓ fibre type I/II ratio ≈ CSA | ||
| Meyer, 2005 [49] | Respiratory | 46 26/20# | IPAH | ↓ PImax, PEmax | ||
| Kabitz, 2008 [47] | Respiratory | 62 31/31# | PH (25 PAH, 6 CTEPH) | ↓ PImax, PEmax, SnPna, SnPdi, TwPmo, TwPdi | ||
| Mainguy, 2010 [48] | Peripheral (M. quadriceps) | 20 10/10# | IPAH | ↓ maximal voluntary contraction (volitional), quadriceps twitch (non-volitional) | ↓ fibre type I/II ratio, PFK/HADH ratio ≈ capillary density, CS, CSA, HADH, PFK/CS ratio | |
| de Man, 2011 [50] | Respiratory (diaphragm) Peripheral (EDL or M. quadriceps) | 12 6/6# 15 8/7# | PH | MCT60 | Patient diaphragm: ↓ maximal isometric force Animal model diaphragm: single muscle fibres: ↓ twitch force, tetanic force, force–frequency Peripheral muscle: ≈ twitch force, tetanic force, force–frequency | Patients' diaphragm: ↓ CSA diaphragm ≈ CSA quadriceps Animal model diaphragm: ↓ CSA ≈ capillary density, SDH, Akt phosphorylation, MHC expression, 20 s proteasome, proteasome activity ↑ MAFbx, MuRF-1 Peripheral muscle: ≈ CSA |
| Manders, 2012 [52] | Respiratory (diaphragm) Peripheral (EDL) | 14 7/7# | MCT60 | Diaphragm: single muscle fibres Fast twitch fibres ↓: maximal tension, calcium sensitivity, force per cross-bridge ≈: fraction strongly bound cross-bridges, tension cost Peripheral muscle: ≈: maximal tension, calcium sensitivity | Diaphragm ↓: fibre type I/II ratio, nitrosative stress ≈: oxidative stress | |
| Wüst, 2012 [54] | Peripheral (M. plantaris) | 23 11/12# | MCT60 | ↓: CSA, complex I activity, SDH ≈: fibre type I/II ratio, capillary density | ||
| Batt, 2014 [53] | Peripheral (M. quadriceps) | 20 10/10# | PAH (IPAH + PAH 1 year after ASD repair) | Overall ↓: CSA, fibre type I/II ratio Regulators muscle mass ↓: pAkt, p-p70S6kinase, pFOXO 3 ≈: pGSK3β ↑: Atrogin-1, MuRF1 Mitochondrial fusion ↓: Mitofusin 1 and 2; ≈: DRP Mitochondrial biogenesis ≈: PGC1α, MtCO2, NRF-1, TFA Calcium cycling ↑: pRyR ≈: SERCA2a, SERCA | ||
| Potus, 2014 [55] | Peripheral (M. quadriceps) | 40 20/20# | PAH (16 IPAH, 4 HPAH) | ↓: quadriceps endurance | ↓: ERK activity, capillary density, miR-126, RAF activity ≈: CSA, fibre type I/II ratio, VEGF, VEGFR2 ↑: SPRED-1 | |
| Manders, 2015 [57] | Peripheral (M. quadriceps) | 19 11/8# | IPAH | Single muscle fibres: ↓: maximal tension, number of attached cross-bridges during activation ≈: fraction strongly bound cross-bridges, force per cross-bridge, calcium sensitivity ↑: passive stiffness | ||
| Manders, 2016 [51] | Respiratory (diaphragm) | 28 13/15# | CTEPH | Single muscle fibres: Slow-twitch fibres: ↓: maximal tension, number of attached cross-bridges during activation Fast-twitch fibres: ↓: calcium sensitivity, submaximal tension ≈: force per cross-bridge | ↓: MHC concentration (slow-twitch fibres) ≈: CSA |
↓: reduction; ↑: increase; ≈: no change; EDL: extensor digitorum longus (peripheral muscle); MCT: monocrotaline; CSA: cross-sectional area; IPAH: idiopathic pulmonary arterial hypertension; PImax (volitional): maximal inspiratory mouth pressure; PEmax (volitional): expiratory mouth pressure; PH: pulmonary hypertension; PAH: pulmonary arterial hypertension; CTEPH: chronic thromboembolic pulmonary hypertension; SnPna (volitional): sniff nasal pressure; SnPdi (volitional): sniff transdiaphragmatic pressure; TwPmo (non-volitional): twitch mouth pressure; TwPdi (non-volitional): transdiaphragmatic pressure; PFK/HADH: β-oxidation of fatty acids; CS: citrate synthase; HADH: 3-hydroxyacyl-coA-dehydrogenase; PFK/CS: glycolysis to citric acid cycle; SDH: succinate dehydrogenase (oxidative enzyme activity); Akt: protein kinase B; MHC: myosin heavy chain; MAFbx/MuRF-1: E3-ligases; MuRF: muscle RING-finger protein; ASD: atrial septum defect; DRP: dynamin-related protein; PGC1α: peroxisome proliferator-activated receptor-γ coactivator; GSK3β: glycogen synthase kinase 3β; MtCO2: mitochondrial encoded cytochrome C oxidase subunit II; NRF-1: nuclear respiratory factor 1; RyR: ryanodine receptor; SERCA: sarco/endoplasmic reticulum Ca2+-ATPase; HPAH: hereditary PAH; ERK: extracellular signal-regulated kinase; miR-126: microRNA126; VEGF: vascular endothelial growth factor; VEGFR2: VEGF receptor type 2; SPRED1: Sprouty-related EVH1 domain-containing protein 1. #: for numbers displayed as “x/y”, x is number of patients, y is number of controls.