Diaphragmatic free radical generation increases in an animal model of heart failure

Supinski, Gerald S.; Callahan, Leigh Ann

doi:10.1152/japplphysiol.01145.2004

Cited by 35 publications

(66 citation statements)

References 33 publications

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“…Sepsis also increases serum SMase activity (53) and causes respiratory muscle weakness (50). In heart failure and sepsis, oxidants are increased in skeletal muscle (24,34,51), and diaphragm muscle weakness is blunted by antioxidant treatment (15,51). These effects are similar to those we found with SMase exposure in vitro.…”

Section: Discussionsupporting

confidence: 79%

Sphingomyelinase stimulates oxidant signaling to weaken skeletal muscle and promote fatigue

Ferreira

Moylan

Gilliam

et al. 2010

American Journal of Physiology-Cell Physiology

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Sphingomyelinase (SMase) hydrolyzes membrane sphingomyelin into ceramide, which increases oxidants in nonmuscle cells. Serum SMase activity is elevated in sepsis and heart failure, conditions where muscle oxidants are increased, maximal muscle force is diminished, and fatigue is accelerated. We tested the hypotheses that exogenous SMase and accumulation of ceramide in muscle increases oxidants in muscle cells, depresses specific force of unfatigued muscle, and accelerates the fatigue process. We also anticipated that the antioxidant N-acetylcysteine (NAC) would prevent SMase effects on muscle function. We studied the responses of C2C12 myotubes and mouse diaphragm to SMase treatment in vitro. We observed that SMase caused a 2.8-fold increase in total ceramide levels in myotubes. Exogenous ceramide and SMase elevated oxidant activity in C2C12 myotubes by 15-35% (P < 0.05) and in diaphragm muscle fiber bundles by 58-120% (P < 0.05). The SMase-induced increase in diaphragm oxidant activity was prevented by NAC. Exogenous ceramide depressed diaphragm force by 55% (P < 0.05), while SMase depressed maximal force by 30% (P < 0.05) and accelerated fatigue--effects opposed by treatment with NAC. In conclusion, our findings suggest that SMase stimulates a ceramide-oxidant signaling pathway that results in muscle weakness and fatigue.

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Section: Discussionsupporting

confidence: 79%

Sphingomyelinase stimulates oxidant signaling to weaken skeletal muscle and promote fatigue

Ferreira

Moylan

Gilliam

et al. 2010

American Journal of Physiology-Cell Physiology

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“…Based on unchanged gene expression of diaphragm SMases, we consider that post-translational modifications activate SMase in CHF (e.g., oxidation or phosphorylation) (12). For example, TNF-α (8) and oxidative stress (25) are elevated in CHF and could be responsible for activation of N-SMase in the diaphragm (12). The increased diaphragm N-SMase activity in CHF is expected to elevate ceramide and metabolites downstream of ceramide.…”

Section: Discussionmentioning

confidence: 99%

Diaphragm dysfunction in heart failure is accompanied by increases in neutral sphingomyelinase activity and ceramide content

Empinado

Deevska

Nikolova‐Karakashian

et al. 2014

European J of Heart Fail

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Aims Chronic heart failure (CHF) causes inspiratory (diaphragm) muscle weakness and fatigue that contributes to dyspnoea and limited physical capacity in patients. However, the mechanisms that lead to diaphragm dysfunction in CHF remain poorly understood. Cytokines and angiotensin II are elevated in CHF and stimulate the activity of the enzyme sphingomyelinase (SMase) and accumulation of its reaction product ceramide. In the diaphragm, SMase or ceramide exposure in vitro causes weakness and fatigue. Thus, elevated SMase activity and ceramide content have been proposed as mediators of diaphragm dysfunction in CHF. In the present study, we tested the hypotheses that diaphragm dysfunction was accompanied by increases in diaphragm SMase activity and ceramide content. Methods and results We used myocardial infarction to induce CHF in rats. We measured diaphragm isometric force, SMase activity by high-performance liquid chromatography, and ceramide subspecies and total ceramide using mass spectrometry. CHF depressed diaphragm force and accelerated fatigue. Diaphragm neutral SMase activity was increased by 20% in CHF, while acid SMase activity was unchanged. We also found that CHF increased the content of C18-, C20, and C24-ceramide subspecies and total ceramide. Downstream of ceramide degradation, diaphragm sphingosine was unchanged, and sphingosine-1-phosphate (S1P) was increased in CHF. Conclusion Our major novel finding was that diaphragm dysfunction in CHF rats was accompanied by higher diaphragm neutral SMase activity, which is expected to cause the observed increase in diaphragm ceramide content.

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“…However, a surrogate of diaphragmatic Vo 2 , the tension-time index, is markedly elevated in patients with CHF, reaching high-fatigue levels during maximal exercise [13]. Recent experimental studies indicate that CHF increases diaphragmatic free radical generation, and the oxidative stress may reduce diaphragm strength [44]. In fact, oxidative stress is a contributing factor to respiratory muscle fatigue, which occurs during heavy exercise in healthy individuals [45].…”

Section: Putative Mechanisms By Which Imt May Improve Exercise Capacimentioning

confidence: 99%

Respiratory muscle function and exercise intolerance in heart failure

Ribeiro

Chiappa²,

Neder³

et al. 2009

Curr Heart Fail Rep

105

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Inspiratory muscle weakness (IMW) is prevalent in patients with chronic heart failure (CHF) caused by left ventricular systolic dysfunction, which contributes to reduced exercise capacity and the presence of dyspnea during daily activities. Inspiratory muscle strength (estimated by maximal inspiratory pressure) has independent prognostic value in CHF. Overall, the results of trials with inspiratory muscle training (IMT) indicate that this intervention improves exercise capacity and quality of life, particularly in patients with CHF and IMW. Some benefit from IMT may be accounted for by the attenuation of the inspiratory muscle metaboreflex. Moreover, IMT results in improved cardiovascular responses to exercise and to those obtained with standard aerobic training. These findings suggest that routine screening for IMW is advisable in patients with CHF, and specific IMT and/or aerobic training are of practical value in the management of these patients.

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Diaphragmatic free radical generation increases in an animal model of heart failure

Cited by 35 publications

References 33 publications

Sphingomyelinase stimulates oxidant signaling to weaken skeletal muscle and promote fatigue

Sphingomyelinase stimulates oxidant signaling to weaken skeletal muscle and promote fatigue

Diaphragm dysfunction in heart failure is accompanied by increases in neutral sphingomyelinase activity and ceramide content

Respiratory muscle function and exercise intolerance in heart failure

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