Diaphragm single-fiber weakness and loss of myosin in congestive heart failure rats

Hees, Hieronymus W. H. van; Heijden, Erik H F M van der; Ottenheijm, Coen A.C.; Heunks, Leo; Pigmans, Cindy J. C.; Verheugt, Freek W.A.; Brouwer, René M.H.J.; Dekhuijzen, P.N.R.

doi:10.1152/ajpheart.00085.2007

Cited by 71 publications

(124 citation statements)

References 61 publications

(87 reference statements)

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“…The loss of diaphragm function during the development of HF may therefore be due, in part, to changes to the contractile elements of the muscle fibers composing the diaphragm. Previous work has demonstrated that the diaphragm of rats in end-stage heart failure can contain less myosin (66) and increased levels of myosin heavy chain oxidation (8). These studies indicate that the myofilament is playing a role in diaphragm dysfunction during heart failure.…”

Section: Diaphragmatic Myofilament Function Becomes Increasingly Impamentioning

confidence: 70%

“…Indeed, this work suggests, for the first time, that a decrease in the phosphorylation state of multiple myofilament proteins may be involved in initiating diaphragm dysfunction during the development of heart failure. Previously, loss of myosin content (66) and/or the increased levels of myosin heavy chain oxidation (8) have been described. While we did not observe any change in total myosin heavy chain content, given the progressive nature of the disease, our results do not preclude this from occurring at a later stage.…”

Section: Discussionmentioning

confidence: 99%

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Dissecting the role of the myofilament in diaphragm dysfunction during the development of heart failure in mice

Gillis

Klaiman

Foster

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Gillis TE, Klaiman JM, Foster A, Platt MJ, Huber JS, Corso MY, Simpson JA. Dissecting the role of the myofilament in diaphragm dysfunction during the development of heart failure in mice. Am J Physiol Heart Circ Physiol 310: H572-H586, 2016. First published December 23, 2015 doi:10.1152/ajpheart.00773.2015.-Dyspnea and reduced exercise capacity, caused, in part, by respiratory muscle dysfunction, are common symptoms in patients with heart failure (HF). However, the etiology of diaphragmatic dysfunction has not been identified. To investigate the effects of HF on diaphragmatic function, models of HF were surgically induced in CD-1 mice by transverse aortic constriction (TAC) and acute myocardial infarction (AMI), respectively. Assessment of myocardial function, isolated diaphragmatic strip function, myofilament force-pCa relationship, and phosphorylation status of myofilament proteins was performed at either 2 or 18 wk postsurgery. Echocardiography and invasive hemodynamics revealed development of HF by 18 wk postsurgery in both models. In vitro diaphragmatic force production was preserved in all groups while morphometric analysis revealed diaphragmatic atrophy and fibrosis in 18 wk TAC and AMI groups. Isometric force-pCa measurements of myofilament preparations revealed reduced Ca 2ϩ sensitivity of force generation and force generation at half-maximum and maximum Ca 2ϩ activation in 18 wk TAC. The rate of force redevelopment (k tr) was reduced in all HF groups at high levels of Ca 2ϩ activation. Finally, there were significant changes in the myofilament phosphorylation status of the 18 wk TAC group. This includes a decrease in the phosphorylation of troponin T, desmin, myosin light chain (MLC) 1, and MLC 2 as well as a shift in myosin isoforms. These results indicate that there are multiple changes in diaphragmatic myofilament function, which are specific to the type and stage of HF and occur before overt impairment of in vitro force production.calcium-activated force generation; diaphragm function; heart failure; myofilament proteins; protein phosphorylation HEART FAILURE (HF) is a global health problem and is one of the most prevalent causes of morbidity in all ages (15,46). Patients with HF are frequently limited in their daily activities by dyspnea and exertional fatigue. One potential cause is inspiratory muscle (primarily the diaphragm) dysfunction. De Troyer and colleagues (11) first noted compromised inspiratory muscle function in patients with cardiac dysfunction. Respiratory muscle dysfunction is now considered a salient feature of patients (11,21,23,35,36,62) and animals (7-9, 24, 28, 53, 58) with HF. Currently, little is known about the development of respiratory muscle dysfunction during the early onset of HF.In patients with HF, eupneic pressure generation is increased (28, 58), which is considered to impose a stress on the diaphragm. This chronic workload on the diaphragm is thought to overwork the muscle leading to development of a myopathy characterized by a shift in fiber type, atrophy, and co...

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Section: Diaphragmatic Myofilament Function Becomes Increasingly Impamentioning

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Dissecting the role of the myofilament in diaphragm dysfunction during the development of heart failure in mice

Gillis

Klaiman

Foster

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…According to previously described methods (5,13), single fiber contractile measurements and experimental protocol were performed as follows.…”

Section: Single Fiber Contractile Measurementsmentioning

confidence: 99%

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

Hees¹,

Dekhuijzen²,

Heunks³

2009

Am J Respir Crit Care Med

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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.

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“…Impaired force generation of the respiratory muscles has been recognized in a variety of diseases, including chronic obstructive pulmonary disease (COPD) and congestive heart failure, and in critically ill patients (1)(2)(3)(4)(5)(6)(7). The pathophysiological substrate of diaphragm dysfunction in these disorders is multifactorial and includes muscle fiber atrophy and contractile protein dysfunction (3,(8)(9)(10)(11).…”

mentioning

confidence: 99%

“…In other words, more calcium is needed to develop the same amount of force as in the non-COPD diaphragm, resulting in impaired contractile efficiency of the diaphragm muscle. Subsequent studies have shown that calcium sensitivity is also reduced in the diaphragm of animal models of congestive heart failure and prolonged mechanical ventilation (2,13). Despite a better understanding of respiratory muscle dysfunction in chronic diseases, no drug is available to improve respiratory muscle function in humans.…”

mentioning

confidence: 99%

The Calcium Sensitizer Levosimendan Improves Human Diaphragm Function

Doorduin

Sinderby

Beck

et al. 2012

Am J Respir Crit Care Med

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116

104

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Rationale: Acquired diaphragm muscle weakness is a key feature in several chronic conditions, including chronic obstructive pulmonary disease, congestive heart failure, and difficult weaning from mechanical ventilation. No drugs are available to improve respiratory muscle function in these patients. Recently, we have shown that the calcium sensitizer levosimendan enhances the force-generating capacity of isolated diaphragm fibers. Objectives: To investigate the effects of the calcium sensitizer levosimendan on in vivo human diaphragm function. Methods: In a double-blind, randomized, crossover design, 30 healthy subjects performed two identical inspiratory loading tasks. After the first loading task, subjects received levosimendan (40 mg/kg bolus followed by 0.1/0.2 mg/kg/min continuous infusion) or placebo. Transdiaphragmatic pressure, diaphragm electrical activity, and their relationship (neuromechanical efficiency) were measured during loading. Magnetic phrenic nerve stimulation was performed before the first loading task and after bolus administration to assess twitch contractility. Center frequency of diaphragm electrical activity was evaluated to study the effects of levosimendan on muscle fiber conduction velocity. Measurements and Main Results:The placebo group showed a 9% (P ¼ 0.01) loss of twitch contractility after loaded breathing, whereas no loss in contractility was observed in the levosimendan group. Neuromechanical efficiency of the diaphragm during loading improved by 21% (P , 0.05) in the levosimendan group. Baseline center frequency of diaphragm electrical activity was reduced after levosimendan administration (P , 0.05). Conclusions: The calcium sensitizer levosimendan improves neuromechanical efficiency and contractile function of the human diaphragm. Our findings suggest a new therapeutic approach to improve respiratory muscle function in patients with respiratory failure.

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Diaphragm single-fiber weakness and loss of myosin in congestive heart failure rats

Cited by 71 publications

References 61 publications

Dissecting the role of the myofilament in diaphragm dysfunction during the development of heart failure in mice

Dissecting the role of the myofilament in diaphragm dysfunction during the development of heart failure in mice

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

The Calcium Sensitizer Levosimendan Improves Human Diaphragm Function

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