title: Diaphragm weakness in pulmonary arterial hypertension: role of sarcomeric dysfunction.
abstract: We previously demonstrated that diaphragm muscle weakness is present in experimental pulmonary arterial hypertension (PH). However, the nature of this diaphragm weakness is still unknown. Therefore, the aim of this study was to investigate whether changes at the sarcomeric level contribute to diaphragm weakness in PH. For this purpose, in control rats and rats with monocrotaline-induced PH, contractile performance and myosin heavy chain content of demembranated single diaphragm fibers were determined. We observed a reduced maximal tension of 20% (P < 0.05), whereas tension cost was preserved in type 2X and 2B diaphragm fibers in PH compared with control. The reduced maximal tension was associated with a reduction of force generated per half-sarcomeric myosin heavy chain content. Additionally, reduced Ca(2+) sensitivity of force generation was found in type 2X fibers compared with control, which could exacerbate diaphragm muscle weakness at submaximal activation. No changes in maximal tension and Ca(2+) sensitivity of force generation were observed in fibers from the nonrespiratory extensor digitorum longus muscle. Together, these findings indicate that diaphragm weakness in PH is at least partly caused by sarcomeric dysfunction, which appears to be specific for the diaphragm.
authors.affiliation: Department of Pulmonology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Emmy
authors.initials: E
authors.lastname: Manders
authors.forename: Frances S
authors.initials: FS
authors.lastname: de Man
authors.forename: M L
authors.initials: ML
authors.lastname: Handoko
authors.forename: Nico
authors.initials: N
authors.lastname: Westerhof
authors.forename: Hieronymus W H
authors.initials: HW
authors.lastname: van Hees
authors.forename: Ger J M
authors.initials: GJ
authors.lastname: Stienen
authors.forename: Anton
authors.initials: A
authors.lastname: Vonk-Noordegraaf
authors.forename: Coen A C
authors.initials: CA
authors.lastname: Ottenheijm
mesh_terms: D000818:Animals; D002118:Calcium / Q000494:pharmacology; D003964:Diaphragm / Q000187:drug effects / Q000503:physiopathology*; D065627:Familial Primary Pulmonary Hypertension; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D016686:Monocrotaline / Q000633:toxicity; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000502:physiology; D018908:Muscle Weakness / Q000139:chemically induced / Q000503:physiopathology*; D018995:Myosin Heavy Chains / Q000032:analysis / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012518:Sarcomeres / Q000187:drug effects / Q000502:physiology*
chemical_list: D016686:Monocrotaline; D018995:Myosin Heavy Chains; D002118:Calcium