Manders E, de Man FS, Handoko ML, Westerhof N, van Hees HW, Stienen GJ, Vonk-Noordegraaf A, Ottenheijm CA. Diaphragm weakness in pulmonary arterial hypertension: role of sarcomeric dysfunction. Am J Physiol Lung Cell Mol Physiol 303: L1070-L1078, 2012. First published September 7, 2012 doi:10.1152/ajplung.00135.2012.-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 Ͻ 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 2ϩ 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 2ϩ 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. single fiber; cross bridge cycling kinetics; Ca 2ϩ sensitivity; myosin heavy chain PULMONARY ARTERIAL HYPERTENSION (PH) is characterized by a progressive increase in pulmonary vascular resistance, ultimately leading to right heart failure and death. Patients with PH hyperventilate at rest, during exercise, and sometimes even during sleep (19,27). As a consequence, inspiratory muscle activity increases substantially, which may ultimately lead to overloading of the inspiratory muscles and respiratory muscle weakness.Recent studies have found markedly lower maximal inspiratory pressures in patients with PH compared with control subjects (19,25). This indicates that the force-generating capacity of the inspiratory muscles is impaired. The presence of inspiratory muscle weakness in PH was further supported by recent work from our group on a rat model for PH, which revealed a significant reduction in twitch and maximal tetanic force generation of the diaphragm, the main muscle of inspiration (8). Data from De Man et al. (8) also suggests a significant reduction of maximal tension in diaphragm fibers of two patients with PH.Thus evidence is accumulating that the diaphragm is weakened in PH. However, the nature of this diaphragm weakness is unknown and might involve changes at the level of sarcoplasmic reticulum calcium cycling or content or at levels downstream in the excitation-contraction coupling process, i.e., at the sarcomeric le...