Anabolic effects of exercise training in patients with advanced chronic heart failure (NYHA IIIb): Impact on ubiquitin–protein ligases expression and skeletal muscle size (original) (raw)
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PloS one, 2014
Heart failure (HF) is associated with cachexia and consequent exercise intolerance. Given the beneficial effects of aerobic exercise training (ET) in HF, the aim of this study was to determine if the ET performed during the transition from cardiac dysfunction to HF would alter the expression of anabolic and catabolic factors, thus preventing skeletal muscle wasting. We employed ascending aortic stenosis (AS) inducing HF in Wistar male rats. Controls were sham-operated animals. At 18 weeks after surgery, rats with cardiac dysfunction were randomized to 10 weeks of aerobic ET (AS-ET) or to an untrained group (AS-UN). At 28 weeks, the AS-UN group presented HF signs in conjunction with high TNF-α serum levels; soleus and plantaris muscle atrophy; and an increase in the expression of TNF-α, NFκB (p65), MAFbx, MuRF1, FoxO1, and myostatin catabolic factors. However, in the AS-ET group, the deterioration of cardiac function was prevented, as well as muscle wasting, and the atrophy promoters...
Chronic heart failure and skeletal muscle catabolism: effects of exercise training
International Journal of Cardiology, 2002
Although the clinical picture of cardiac cachexia is well-known in patients with advanced chronic heart failure (CHF) the factors that determine who is at risk for this progressive catabolic syndrome and who is not remain unclear. Different endocrine systems have been accused of being involved in this process: an imbalance between catabolic and anabolic steroids with an elevated cortisol / dihydroepiandrosterone ratio, an increased resting metabolic rate due to high levels of circulating catecholamines, various cytokines are activated in CHF (i.e. TNF-a, IL-6, IL-1b and others), and elevated levels of growth hormone (GH) with inappropriately normal or low serum levels of insulin-like growth factor-I (IGF-I) have been described in cardiac cachexia. These catabolic factors contribute to peripheral muscle atrophy, augment the expression of the inducible nitric oxide synthase (iNOS), which in turn inhibits the aerobic cellular metabolism. The present review examines whether the catabolic factors can be influenced by a classical anabolic intervention: regular physical exercise training. Long-term training programs increase skeletal muscle cytochrome c oxidase activity and are associated with reduced local expression of pro-inflammatory cytokines as well as iNOS, and augment local IGF-I production. In concert, these beneficial effects of exercise training may help to retard the catabolic process in CHF finally leading to cardiac cachexia and death.
Journal of Cardiac Failure, 2004
Background. We sought to determine whether skeletal muscle oxidative capacity, fiber type proportions and fiber size, capillary density or muscle mass might explain the impaired exercise tolerance in chronic heart failure (CHF). Previous studies are equivocal regarding the maladaptations that occur in the skeletal muscle of patients with CHF and their role in the observed exercise intolerance. Methods and Results. Total body O 2 uptake (peak) was determined in 14 CHF patients and 8 healthy sedentary similarly-aged controls. Muscle samples were analysed for mitochondrial ATP production rate (MAPR), oxidative and glycolytic enzyme activity, fiber size and type, and capillary density. CHF patients demonstrated a lower peak (15.1 ± 1.1 vs. 28.1 ± 2.3 ml.kg & VO 2 & VO 2-1 .min-1 , p<0.001) and capillary to fiber ratio (1.09 ± 0.05 vs. 1.40 ± 0.04; p<0.001) when compared to controls. However there was no difference in capillary density (capillaries per µm 2) across any of the fiber types. Measurements of MAPR and oxidative enzyme activity indicated no difference in muscle oxidative capacity between the groups. Conclusions. Neither reduced muscle oxidative capacity nor capillary density are the cause of exercise limitation in CHF patients. We conclude that the low peak observed in CHF patients is the result of muscle fiber atrophy and possibly impaired activation of oxidative phosphorylation.
Circulation, 1992
Background. The purpose of this study was to investigate the prevalence of skeletal muscle atrophy and its relation to exercise intolerance and abnormal muscle metabolism in patients with heart failure (HF). Methods and Results. Peak Vo2, percent ideal body weight (% IBW), 24-hour urine creatinine (Cr), and anthropometrics were measured in 62 ambulatory patients with HF. 31P magnetic resonance spectroscopy (MRS) and imaging (MRI) of the calf were performed in 15 patients with HF and 10 control subjects. Inorganic phosphorus (Pi), phosphocreatine (PCr), and intracellular pH were measured at rest and during exercise. Calf muscle volume was determined from the sum of the integrated area of muscle in 1-cm-thick contiguous axial images from the patella to the calcaneus. A reduced skeletal muscle mass was noted in 68% of patients, as evidenced by a decrease in Cr-to-height ratio of <7.4 mg/cm and/or upper arm circumference of <5% of normal. Calf muscle volume (MRI) was also reduced in the patients with HF (controls, 675±84 cm3/m2; HF, 567±112 cm3/m2; p<0.05). Fat stores were largely perserved with triceps skinfold of <5% of normal and/or IBW of <80% in only 8% of patients. Modest linear correlations were observed between peak Vo2 and both calf muscle volume per meter squared (r=0.48) and midarm muscle area (r=0.36) (both p<O.05). 31p metabolic abnormalities during exercise were observed in the patients with HF, which is consistent with intrinsic oxidative abnormalities. The metabolic changes were weakly correlated with muscle volume (r=-0.42, p<0.05). Conclusions. These findings indicate that patients with chronic HF frequently develop significant skeletal muscle atrophy and metabolic abnormalities. Atrophy contributes modestly to both the reduced exercise capacity and altered muscle metabolism. (Circulation 1992;85:1364-1373) KEY WoRDs * skeletal muscle * exercise testing * heart failure
Congestive Heart Failure, 2003
Recent studies suggest that changes in the periphery, like those occurring in the skeletal muscles of patients with chronic heart failure, might play an important role in the origin of symptoms and exercise intolerance in this condition. Biochemical and histologic changes in the skeletal muscles of chronic heart failure patients relate with the degree of exercise intolerance better than hemodynamics parameters. A reduction in skeletal muscle mass represents another important determinant of exercise intolerance in chronic heart failure patients. The relationship between skeletal muscle changes and exercise intolerance suggests the possibility of modifying the peripheral changes in order to improve functional capacity in chronic heart failure patients. Recent studies have shown that the administration of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers can improve the properties of the skeletal muscles. Similarly, exercise training allows improvement in peak oxygen consumption, which parallels important biochemical and histologic changes in the skeletal muscles. (CHF. 2003;9:148-154) Chronic heart failure (HF) is a common and debilitating condition with high rates of mortality and morbidity. The prevalence of symptomatic HF in the general European population ranges from 0.4%-2% and is expected to increase as the population ages. 1 Commonly, symptom generation in chronic HF was attributed to central hemodynamic alterations, but other factors, such as skeletal muscle changes, may also play a role. The purpose of the present review is to summarize the available data on the widespread abnormalities which skeletal muscle develops in the course of chronic HF, and to discuss how such alterations may be generated and their role in the onset of the typical symptoms of this condition.
Journal of Cardiac Failure, 2014
Background: Declining physical function is common among systolic heart failure (HF) patients and heralds poor clinical outcomes. We hypothesized that coordinated shifts in expression of ubiquitin-mediated atrophy-promoting genes are associated with muscle atrophy and contribute to decreased physical function. Methods: Systolic HF patients (left ventricular ejection fraction [LVEF] #40%) underwent skeletal muscle biopsies (nondominant vastus lateralis) and comprehensive physical assessments. Skeletal muscle gene expression was assessed with the use of real-time polymerase chain reaction. Aerobic function was assessed with the use of cardiopulmonary exercise and 6-minute walk tests. Strength capacity was assessed with the use of pneumatic leg press (maximum strength and power). Serologic inflammatory markers also were assessed. Results: 54 male patients (66.6 6 10.0 years) were studied: 24 systolic HF patients (mean LVEF 28.9 6 7.8%) and 30 age-matched control subjects. Aerobic and strength parameters were diminished in HF versus control. FoxO1 and FoxO3 were increased in HF versus control (7.9 6 6.2 vs 5.0 6 3.5, 6.5 6 4.3 vs 4.3 6 2.8 relative units, respectively; P #.05 in both). However, atrogin-1 and MuRF-1 were similar in both groups. PGC-1a was also increased in HF (7.9 6 5.4 vs. 5.3 6 3.6 relative units; P ! .05). Muscle levels of insulin-like growth factor (IGF) 1 as well as serum levels of tumor necrosis factor a, C-reactive protein, interleukin (IL) 1b, and IL-6 were similar in HF and control. Conclusion: Expression of the atrophy-promoting genes FoxO1 and FoxO3 were increased in skeletal muscle in systolic HF compared with control, but other atrophy gene expression patterns (atrogin-1 and MuRF-1), as well as growth promoting patterns (IGF-1), were similar. PGC-1a, a gene critical in enhancing mitochondrial function and moderating FoxO activity, may play an important counterregulatory role to offset ubiquitin pathwayemediated functional decrements. (J Cardiac Fail 2014;20:422e430)
Clinical Interventions in Aging, 2012
Background: Heart failure (HF), a debilitating disease in a growing number of adults, exerts structural and neurohormonal changes in both cardiac and skeletal muscles. However, these alterations and their affected molecular pathways remain uncharacterized. Disease progression is known to transform skeletal muscle fiber composition by unknown mechanisms. In addition, perturbation of specific hormonal pathways, including those involving skeletal muscle insulinlike growth factor-1 (IGF-1) and insulin-like growth factor-binding protein-5 (IGFB-5) appears to occur, likely affecting muscle metabolism and regeneration. We hypothesized that changes in IGF-1 and IGFB-5 mRNA levels correlate with the transformation of single-skeletal muscle fiber myosin heavy chain isoforms early in disease progression, making these molecules valuable markers of skeletal muscle changes in heart failure. Materials and methods: To investigate these molecules during "early" events in HF patients, we obtained skeletal muscle biopsies from New York Heart Association (NYHA) Class II HF patients and controls for molecular analyses of single fibers, and we also quantified isometric strength and muscle size. Results: There were more (P , 0.05) single muscle fibers coexpressing two or more myosin heavy chains in the HF patients (30% ± 7%) compared to the control subjects (13% ± 2%). IGF-1 and IGFBP-5 expression was fivefold and 15-fold lower in patients with in HF compared to control subjects (P , 0.05), respectively. Strikingly, there was a correlation in IGF-1 expression and muscle cross-sectional area (P , 0.05) resulting in a decrease in whole-muscle quality (P , 0.05) in the HF patients, despite no significant decrease in isometric strength or whole-muscle size. Conclusion: These data indicate that molecular alterations in myosin heavy chain isoforms, IGF-1, and IGFB-5 levels precede the gross morphological and functional deficits that have previously been associated with HF, and may be used as a predictor of functional outcome in patients.