Diaphragm weakness in pulmonary arterial hypertension: Role of sarcomeric dysfunction

Emmy Manders, Frances S. de Man, M. L. Handoko, Nico Westerhof, Hieronymus W.H. van Hees, Ger J.M. Stienen, Anton Vonk-Noordegraaf, Coen A.C. Ottenheijm

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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 Ca2+ 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 Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)L1070-L1078
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume303
Issue number12
DOIs
StatePublished - Dec 15 2012
Externally publishedYes

Keywords

  • Cas sensitivity
  • Cross bridge cycling kinetics
  • Myosin heavy chain
  • Single fiber

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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