Heart Failure in Rats Causes Changes in Skeletal Muscle Morphology and Gene Expression That Are Not Explained by Reduced Activity

Simonini, Americo; Long, Carlin S.; Dudley, Gary A.; Yue, Ping; McElhinny, Jill; Massie, Barry M.

doi:10.1161/01.res.79.1.128

Cited by 117 publications

(112 citation statements)

References 39 publications

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“…However, multiple studies in animal models and humans have indicated that the skeletal muscle abnormalities found in HFREF patients are not due solely to deconditioning (13,18,49,61,70). Furthermore, deconditioning primarily decreases type II fibers rather than type I fibers (49).…”

Section: Discussionmentioning

confidence: 99%

Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction

Kitzman

Nicklas

Kraus

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

268

229

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Kitzman DW, Nicklas B, Kraus WE, Lyles MF, Eggebeen J, Morgan TM, Haykowsky M. Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction. Am J Physiol Heart Circ Physiol 306: H1364-H1370, 2014. First published March 21, 2014 doi:10.1152/ajpheart.00004.2014.-Heart failure (HF) with preserved ejection fraction (HFPEF) is the most common form of HF in older persons. The primary chronic symptom in HFPEF is severe exercise intolerance, and its pathophysiology is poorly understood. To determine whether skeletal muscle abnormalities contribute to their severely reduced peak exercise O2 consumption (V O2), we examined 22 older HFPEF patients (70 Ϯ 7 yr) compared with 43 age-matched healthy control (HC) subjects using needle biopsy of the vastus lateralis muscle and cardiopulmonary exercise testing to assess muscle fiber type distribution and capillarity and peak V O2. In HFPEF versus HC patients, peak V O2 (14.7 Ϯ 2.1 vs. 22.9 Ϯ 6.6 ml·kg Ϫ1 · min Ϫ1 , P Ͻ 0.001) and 6-min walk distance (454 Ϯ 72 vs. 573 Ϯ 71 m, P Ͻ 0.001) were reduced. In HFPEF versus HC patients, the percentage of type I fibers (39.0 Ϯ 11.4% vs. 53.7 Ϯ 12.4%, P Ͻ 0.001), type I-to-type II fiber ratio (0.72 Ϯ 0.39 vs. 1.36 Ϯ 0.85, P ϭ 0.001), and capillary-to-fiber ratio (1.35 Ϯ 0.32 vs. 2.53 Ϯ 1.37, P ϭ 0.006) were reduced, whereas the percentage of type II fibers was greater (61 Ϯ 11.4% vs. 46.3 Ϯ 12.4%, P Ͻ 0.001). In univariate analyses, the percentage of type I fibers (r ϭ 0.39, P ϭ 0.003), type I-to-type II fiber ratio (r ϭ 0.33, P ϭ 0.02), and capillary-to-fiber ratio (r ϭ 0.59, P Ͻ 0.0001) were positively related to peak V O2. In multivariate analyses, type I fibers and the capillary-to-fiber ratio remained significantly related to peak V O2. We conclude that older HFPEF patients have significant abnormalities in skeletal muscle, characterized by a shift in muscle fiber type distribution with reduced type I oxidative muscle fibers and a reduced capillary-to-fiber ratio, and these may contribute to their severe exercise intolerance. This suggests potential new therapeutic targets in this difficult to treat disorder. heart failure; exercise; aging APPROXIMATELY 50% OF HEART FAILURE (HF) patients living in the community have preserved left ventricular (LV) ejection fraction (HFPEF) (33,52,68). HFPEF is nearly exclusively a disorder of older persons and is most common in women. The primary symptom in patients with chronic HFPEF is severe exercise intolerance, measured objectively as decreased peak exercise O 2 uptake (peak V O 2 ) (2,3,5,26,30,34,35,41), and this is associated with a reduced quality of life. Despite its importance, the pathophysiology of exercise intolerance in HFPEF is not well understood.Several lines of evidence suggest that in older HFPEF patients, noncardiac factors may contribute to reduced peak V O 2 and may be major contributors to the improvement in peak V O 2 after endurance exercise training (2,5,23,24,26,36,47,54). It is known that aging results in alter...

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Section: Discussionmentioning

confidence: 99%

Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction

Kitzman

Nicklas

Kraus

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

268

229

View full text Add to dashboard Cite

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“…3,4,18,19 Most intriguing was the training-induced reduction of the local expression of tumor necrosis factor (TNF)-␣ that is known to diminish intracellular levels of reduced glutathione (ie, glutathione containing an SH group [GSH]), which is an essential cofactor of GPX and hence, decrease GPX activity 11,20,21 ; however, it is currently unknown whether the trainingmediated downregulation of SM inflammation is associated with restoration of the local enzymatic radical scavenger system. Therefore, we aimed to investigate whether aerobic exercise training in stable CHF reconstitutes the activity of SOD, Cat, and GPX, thereby reducing oxidative stress and apoptosis of myocytes in SM.…”

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confidence: 99%

Antioxidative Effects of Exercise Training in Patients With Chronic Heart Failure

et al. 2005

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Background-In chronic heart failure (CHF), cross-talk between inflammatory activation and oxidative stress has been anticipated in skeletal muscle (SM). The role of the radical scavenger enzymes superoxide dismutase (SOD), catalase (Cat), and glutathione peroxidase (GPX), which remove oxygen radicals, has never been assessed in the SM in this context. Moreover, it remains unknown whether exercise training augments the activity of these enzymes in CHF. Methods and Results-Twenty-three patients with CHF were randomized to either 6 months of exercise training (T) or a sedentary lifestyle (C); 12 age-matched healthy subjects (HS) were studied in parallel. Activity of Cat, SOD, and GPX was assessed in SM biopsies before and after 6 months (6 months). Oxidative stress was determined by measuring nitrotyrosine formation. SOD, Cat, and GPX activity was reduced by 31%, 57%, and 51%, respectively, whereas nitrotyrosine formation was increased by 107% in SM in CHF (PϽ0.05 versus HS). In CHF, exercise training augmented GPX and Cat activity in SM by 41% (PϽ0.05 versus before and group C) and 42% (PϽ0.05 versus before and group C), respectively, and decreased nitrotyrosine production by 35% (from 3.8Ϯ0.4% tissue area before to 2.5Ϯ0.3% after 6 months; PϽ0.05 versus before). Conclusions-The reduced activity of major antioxidative enzymes in the SM of CHF patients is associated with increased local oxidative stress. Exercise training exerts antioxidative effects in the SM in CHF, in particular, due to an augmentation in activity of radical scavenger enzymes.

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“…Importantly, evidence indicates that inactivity alone cannot fully account for congestive heart failure-induced reductions in muscle function (25). Recent work indicates, however, that congestive heart failure is associated with an increase in generation of free radicals (i.e., molecules derived from superoxide anions) and other reactive oxygen species in some tissues (2,32).…”

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

Supinski

Callahan²

2005

Journal of Applied Physiology

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Supinski, Gerald S., and Leigh A. Callahan. Diaphragmatic free radical generation increases in an animal model of heart failure. J Appl Physiol 99: 1078 -1084, 2005; doi:10.1152/japplphysiol.01145.2004.-Heart failure evokes diaphragm weakness, but the mechanism(s) by which this occurs are not known. We postulated that heart failure increases diaphragm free radical generation and that free radicals trigger diaphragm dysfunction in this condition. The purpose of the present study was to test this hypothesis. Experiments were performed using halothaneanesthetized sham-operated control rats and rats in which myocardial infarction was induced by ligation of the left anterior descending coronary artery. Animals were killed 6 wk after surgery, the diaphragms were removed, and the following were assessed: 1) mitochondrial hydrogen peroxide (H2O2) generation, 2) free radical generation in resting and contracting intact diaphragm using a fluorescent-indicator technique, 3) 8-isoprostane and protein carbonyls (indexes of free radical-induced lipid and protein oxidation), and 4) the diaphragm force-frequency relationship. In additional experiments, a group of coronary ligation animals were treated with polyethylene glycol-superoxide dismutase (PEG-SOD, 2,000 units⅐kg Ϫ1 ⅐day Ϫ1) for 4 wk. We found that coronary ligation evoked an increase in free radical formation by the intact diaphragm, increased diaphragm mitochondrial H2O2 generation, increased diaphragm protein carbonyl levels, and increased diaphragm 8-isoprostane levels compared with controls (P Ͻ 0.001 for the first 3 comparisons, P Ͻ 0.05 for 8-isoprostane levels). Force generated in response to 20-Hz stimulation was reduced by coronary ligation (P Ͻ 0.05); PEG-SOD administration restored force to control levels (P Ͻ 0.03). These findings indicate that cardiac dysfunction due to coronary ligation increases diaphragm free radical generation and that free radicals evoke reductions in diaphragm force generation. oxidative stress CONGESTIVE HEART FAILURE IS known to evoke significant changes in skeletal muscle function, inducing muscle wasting, reductions in muscle force-generating capacity, and alterations in muscle energy metabolism (9,16,20). Both limb and respiratory skeletal muscle are thought to be affected in this condition (28). Some work indicates that limb skeletal muscle dysfunction plays an important role in determining exercise capacity in patients with congestive heart failure (22). In addition, respiratory muscle dysfunction may predispose these patients to respiratory failure under conditions in which the respiratory workload increases (28).The mechanism by which congestive heart failure alters skeletal muscle function remains unclear. Importantly, evidence indicates that inactivity alone cannot fully account for congestive heart failure-induced reductions in muscle function (25). Recent work indicates, however, that congestive heart failure is associated with an increase in generation of free radicals (i.e., molecules derived from superoxide anions) an...

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Heart Failure in Rats Causes Changes in Skeletal Muscle Morphology and Gene Expression That Are Not Explained by Reduced Activity

Cited by 117 publications

References 39 publications

Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction

Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction

Antioxidative Effects of Exercise Training in Patients With Chronic Heart Failure

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

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