Heart failure-induced skeletal myopathy in spontaneously hypertensive rats

Damatto, Ricardo Luiz; Martinez, Paula Felippe; Lima, A. R. R.; Cezar, M. D. M.; Campos, Dijon Henrique Salomé de; Oliveira, S. A.; Guizoni, Daniele M.; Bonomo, Camila; Nakatani, Bruno Tsutomu; Dal-Pai-Silva, Maeli; Carvalho, Robson Francisco; Okoshi, Katashi; Okoshi, Marina Politi

doi:10.1016/j.ijcard.2012.03.063

Cited by 49 publications

(55 citation statements)

References 55 publications

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“…Although there is substantial evidence that myogenic regulatory factors are changed in HF-induced skeletal myopathy [12,29,36], our hypothesis that MRFs modulate MyHC isoforms distribution in diaphragm was not confirmed. Myogenin is frequently found in association with oxidative enzyme expression and seems to play a role in skeletal metabolism characterization [27,28,59].…”

Section: Discussionmentioning

confidence: 71%

“…At the time of euthanasia, we determined the presence or absence of congestive HF by assessing lung congestion (lung weight/body weight ratio > 2 standard deviations above Sham group mean) and right ventricular hypertrophy (right ventricle weight-to-body weight ratio greater than 0.8 mg/g) [34,35,36]. After euthanasia, the infarcted rats were subdivided in two groups: 1) MI/HF- rats with no evidence of HF (n=10), and 2) MI/HF+ rats with right ventricular hypertrophy and lung congestion (n=10).…”

Section: Methodsmentioning

confidence: 99%

“…Diaphragm protein levels were analyzed by Western blot according to a previously described method [36,44] using specific anti- myogenin (myogenin M-225 sc-576), MyoD (MyoD M-318 sc-760), MRF4 (Myf-6 C-19 sc-301), JNK (JNK 1/2 D-9 sc-137019), p-JNK (p-JNK G-7 sc-6254), p38 (p38 α/β A-12 sc-7972), p-p38 ( p-p38 Thr 180/Tyr 182-R sc-17852-R), ERK (ERK 1 C-16 sc-93), p-ERK (p-ERK 1/2 Thr 202/Tyr 204 sc-16982), NF-κB (p65 NF-κB (sc-7151), p-NF-κB (Ser 536 p-p65 NF-κB sc-33020), IkB (IκB-α sc-1643), and p-IkB (p-IκB-α sc-101713) antibodies (Santa Cruz Biotechnology, Santa Cruz, CA, USA). Protein levels were normalized to GAPDH (6C5 sc-32233, Santa Cruz Biotechnology).…”

Section: Methodsmentioning

confidence: 99%

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Heart Failure-Induced Diaphragm Myopathy

Lima

Martinez

Damatto

et al. 2014

Cell Physiol Biochem

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Background: Intracellular signaling pathways involved in skeletal myosin heavy chain (MyHC) isoform alterations during heart failure (HF) are not completely understood. We tested the hypothesis that diaphragm expression of mitogen-activated protein kinases (MAPK) and myogenic regulatory factors is changed in rats with myocardial infarction (MI) induced HF. Methods: Six months after MI rats were subjected to transthoracic echocardiography. After euthanasia, infarcted rats were subdivided in MI/HF- group (with no HF evidence; n=10), and MI/HF+ (with right ventricular hypertrophy and lung congestion; n=10). Sham-operated rats were used as controls (n=10). MyHC isoforms were analyzed by electrophoresis. Statistical analysis: ANOVA and Pearson correlation. Results: MI/HF- had left cardiac chambers dilation with systolic and diastolic left ventricular dysfunction. Cardiac injury was more intense in MI/HF+ than MI/HF-. MyHC I isoform percentage was higher in MI/HF+ than MI/HF-, and IIb isoform lower in MI/HF+ than Sham. Left atrial diameter-to-body weight ratio positively correlated with MyHC I (p=0.005) and negatively correlated with MyHC IIb (p=0.02). TNF-a serum concentration positively correlated with MyHC I isoform. Total and phosphorylated ERK was lower in MI/HF- and MI/HF+ than Sham. Phosphorylated JNK was lower in MI/HF- than Sham. JNK and p38 did not differ between groups. Expression of NF-κB and the myogenic regulatory factors MyoD, myogenin, and MRF4 was similar between groups. Conclusion: Diaphragm MyHC fast-to-slow shift is related to cardiac dysfunction severity and TNF-a serum levels in infarcted rats. Reduced ERK expression seems to participate in MyHC isoform changes. Myogenic regulatory factors and NF-κB do not modulate diaphragm MyHC distribution during chronic HF.

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Section: Discussionmentioning

confidence: 71%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Heart Failure-Induced Diaphragm Myopathy

Lima

Martinez

Damatto

et al. 2014

Cell Physiol Biochem

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“…32 We have observed in heart failure rats that muscle atrophy was combined with changes in myostatin/follistatin expression. 22,33 Muscle disuse by bed rest can also contribute to protein catabolism. 26 The most important consequence of increased protein degradation is a reduction in myocyte cross-sectional area and muscle mass, which contributes to a reduction in physical performance and daily living activities.…”

Section: Imbalance Between Anabolic and Catabolic Processesmentioning

confidence: 99%

“…40 Also in heart failure, muscle loss pattern depends on experimental model, and both a slow-to-fast and a fast-to-slow fiber-type shift has been described. 33,41 Recently, Callahan and Toth 26 suggested that increased proteolysis and reduced protein synthesis mainly occur during disease exacerbation and hospitalization due to increased inflammatory and neurohormonal activation. As anabolic pathways are probably insufficient to recover muscle size and function to prehospitalization levels, efforts to prevent disease exacerbation should be emphasized.…”

Section: Imbalance Between Anabolic and Catabolic Processesmentioning

confidence: 99%

Cardiac cachexia and muscle wasting: definition, physiopathology, and clinical consequences

Okoshi¹,

Romeiro²,

Martínez³

et al. 2014

RRCC

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Cachexia and muscle wasting are frequently observed in heart failure patients. Cachexia is a predictor of reduced survival, independent of important parameters such as age, heart failure functional class, and functional capacity. Muscle and fat wasting can also predict adverse outcome during cardiac failure. Only more recently were these conditions defined in International Consensus. Considering that heart failure is an inflammatory disease, cardiac cachexia has been diagnosed by finding a body weight loss .5%, in the absence of other diseases and independent of other criteria. Muscle wasting has been defined as lean appendicular mass corrected for height squared of 2 standard deviations or more below the mean for healthy individuals between 20 years and 30 years old from the same ethnic group. The etiology of heart failure-associated cachexia and muscle wasting is multifactorial, and the underlying physiopathological mechanisms are not completely understood. The most important factors are reduced food intake, gastrointestinal alterations, immunological activation, neurohormonal abnormalities, and an imbalance between anabolic and catabolic processes. Cachexia and muscle wasting have clinical consequences in several organs and systems including the gastrointestinal and erythropoietic systems, and the heart, previously affected by the primary disease. We hope that a better understanding of the mechanisms involved in their physiopathology will allow the development of pharmacological and nonpharmacological therapies to effectively prevent and treat heart failure-induced cachexia and muscle wasting before significant body weight and muscle wasting occurs.

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Effects of aerobic and inspiratory training on skeletal muscle microRNA‐1 and downstream‐associated pathways in patients with heart failure

Antunes‐Correa

Trevizan

Bacurau

et al. 2019

J cachexia sarcopenia muscle

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Background The exercise intolerance in chronic heart failure with reduced ejection fraction (HFrEF) is mostly attributed to alterations in skeletal muscle. However, the mechanisms underlying the skeletal myopathy in patients with HFrEF are not completely understood. We hypothesized that (i) aerobic exercise training (AET) and inspiratory muscle training (IMT) would change skeletal muscle microRNA‐1 expression and downstream‐associated pathways in patients with HFrEF and (ii) AET and IMT would increase leg blood flow (LBF), functional capacity, and quality of life in these patients. Methods Patients age 35 to 70 years, left ventricular ejection fraction (LVEF) ≤40%, New York Heart Association functional classes II–III, were randomized into control, IMT, and AET groups. Skeletal muscle changes were examined by vastus lateralis biopsy. LBF was measured by venous occlusion plethysmography, functional capacity by cardiopulmonary exercise test, and quality of life by Minnesota Living with Heart Failure Questionnaire. All patients were evaluated at baseline and after 4 months. Results Thirty‐three patients finished the study protocol: control (n = 10; LVEF = 25 ± 1%; six males), IMT (n = 11; LVEF = 31 ± 2%; three males), and AET (n = 12; LVEF = 26 ± 2%; seven males). AET, but not IMT, increased the expression of microRNA‐1 (P = 0.02; percent changes = 53 ± 17%), decreased the expression of PTEN (P = 0.003; percent changes = −15 ± 0.03%), and tended to increase the p‐AKTser473/AKT ratio (P = 0.06). In addition, AET decreased HDAC4 expression (P = 0.03; percent changes = −40 ± 19%) and upregulated follistatin (P = 0.01; percent changes = 174 ± 58%), MEF2C (P = 0.05; percent changes = 34 ± 15%), and MyoD expression (P = 0.05; percent changes = 47 ± 18%). AET also increased muscle cross‐sectional area (P = 0.01). AET and IMT increased LBF, functional capacity, and quality of life. Further analyses showed a significant correlation between percent changes in microRNA‐1 and percent changes in follistatin mRNA (P = 0.001, rho = 0.58) and between percent changes in follistatin mRNA and percent changes in peak VO2 (P = 0.004, rho = 0.51). Conclusions AET upregulates microRNA‐1 levels and decreases the protein expression of PTEN, which reduces the inhibitory action on the PI3K‐AKT pathway that regulates the skeletal muscle tropism. The increased levels of microRNA‐1 also decreased HDAC4 and increased MEF2c, MyoD, and follistatin expression, improving skeletal muscle regeneration. These changes associated with the increase in muscle cross‐sectional area and LBF contribute to the attenuation in skeletal myopathy, and the improvement in functional capacity and quality of life in patients with HFrEF. IMT caused no changes in microRNA‐1 and in the downstream‐associated pathway. The increased functional capacity provoked by IMT seems to be associated with amelioration in the respiratory function instead of changes in skeletal muscle. http://ClinicalTrials.gov (Identifier: NCT01747395)

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Heart failure-induced skeletal myopathy in spontaneously hypertensive rats

Abstract: Reduced myogenin and follistatin expression seems to participate in muscle atrophy while increased MRF4 protein levels can modulate myosin heavy chain isoform shift in skeletal muscle of spontaneously hypertensive rats with heart failure.

Cited by 49 publications

References 55 publications

Heart Failure-Induced Diaphragm Myopathy

Heart Failure-Induced Diaphragm Myopathy

Cardiac cachexia and muscle wasting: definition, physiopathology, and clinical consequences

Effects of aerobic and inspiratory training on skeletal muscle microRNA‐1 and downstream‐associated pathways in patients with heart failure

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