Levosimendan Enhances Force Generation of Diaphragm Muscle from Patients with Chronic Obstructive Pulmonary Disease

Abstract

Rationale: Levosimendan is clinically used to improve myocardial contractility by enhancing calcium sensitivity of force generation. The effects of levosimendan on skeletal muscle contractility are unknown. Patients with chronic obstructive pulmonary disease (COPD) suffer from diaphragm weakness, which is associated with decreased calcium sensitivity. Objectives: To investigate the effects of levosimendan on contractility of diaphragm fibers from patients with COPD. Methods: Muscle fibers were isolated from diaphragm biopsies obtained from thoracotomized patients with and without COPD (both groups n 5 5, 10 fibers per patient). Diaphragm fibers were skinned and activated with solutions containing incremental calcium concentrations and 10 mM levosimendan or vehicle (0.02% dimethyl sulfoxide). Developed force was measured at each step and force versus calcium concentration relationships were derived. Results were grouped per myosin heavy chain isoform, which was determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Measurements and Main Results: At sub-maximal activation levosimendan improved force generation of COPD and non-COPD diaphragm fibers by approximately 25%, both in slow and fast fibers. Levosimendan increased calcium sensitivity of force generation (P , 0.01) in both slow and fast diaphragm fibers from patients with and without COPD, without affecting maximal force generation. Conclusions: Levosimendan enhances force generating capacity of diaphragm fibers from patients with and without COPD patients by increasing calcium sensitivity of force generation. These results provide a strong rationale for testing the effect of calcium sensitizers on respiratory muscle dysfunction in patients with COPD.

Respiratory muscle fiber remodeling in chronic hyperinflation: dysfunction or adaptation?

“…The changes in twitch force observed in some studies are also consistent with the observation from Ottenheijm et al (62) that fibers from patients with mild to moderate COPD have lower Ca 2ϩ sensitivities in both type I and IIA fibers. This has recently been confirmed by the same group in another set of mild to moderate COPD patients (86). Interestingly, changes in Ca 2ϩ sensitivity cannot be solely explained by the more oxidative characteristics of diaphragm fibers in COPD, as discussed below.…”

“…The largest exceptions to this are the work of Lewis et al (43), who showed reductions in in vitro specific force of Ͼ20%, and Huenks et al (32), who demonstrated reductions of ϳ14%. In human studies of isolated fibers from biopsy specimens, two groups, Levine et al (40) and Ottenheijm et al (64), have found significant reductions in specific force in individual costal diaphragm fibers (Table 2), an observation recently confirmed in another group of COPD patients by these authors (86 1, increase; 2, decrease; TLC, total lung capacity; FRC, functional residual capacity;…”

“…It is a characteristic that would be responsible to pharmacological treatment. In a recent study, the cardiac drug, levosimendan, the only pharmacological Ca 2ϩ sensitizer approved for human use at this time, has been shown to improve the Ca 2ϩ sensitivity of isolated biopsies of diaphragm from COPD patients (86).…”

Diaphragm Muscle Fiber Weakness and Ubiquitin–Proteasome Activation in Critically Ill Patients

“…Consequently, it is unknown whether these findings translate to critically ill patients. Establishing whether in critically ill patients the individual diaphragm muscle fibers exhibit contractile weakness is of utmost importance, because this provides rationale for treatment strategies that specifically improve the contractility of diaphragm fibers to facilitate weaning (27)(28)(29).…”

Muscle Fatigue from the Perspective of a Single Crossbridge

“…20,24,26,46,[58][59][60] Characterizing the mechanisms of fatigue at the cellular and molecular levels is important because many of the most promising therapeutic interventions act at this level to attenuate the debilitating effects of fatigue in clinical populations. 30, 51,57,74,87 In addition to directly inhibiting the crossbridge cycle, the metabolic by-products that are elevated during intense contractile activity are thought to indirectly affect contractile function by altering the ability of the muscle regulatory proteins (troponin [Tn] and tropomyosin [Tm]) to regulate actomyosin binding by making the thin filament less sensitive to Ca 2+ . 26,32,56,59 This mechanism is thought to play a particularly prominent role in fatigue at higher stimulation rates when the myoplasmic Ca 2+ concentration is rapidly compromised and muscular force drops precipitously.…”