Exercise: a molecular tool to boost muscle growth and mitochondrial performance in heart failure?

A significant proportion of heart failure patients develop skeletal muscle wasting and cardiac cachexia, which is associated with a very poor prognosis. Recently, myostatin, a cytokine from the transforming growth factor-β (TGF-β) family and a known strong inhibitor of skeletal muscle growth, has been identified as a direct mediator of skeletal muscle atrophy in mice with heart failure. Myostatin is mainly expressed in skeletal muscle, although basal expression is also detectable in heart and adipose tissue. During pathological loading of the heart, the myocardium produces and secretes myostatin into the circulation where it inhibits skeletal muscle growth. Thus, genetic elimination of myostatin from the heart reduces skeletal muscle atrophy in mice with heart failure, whereas transgenic overexpression of myostatin in the heart is capable of inducing muscle wasting. In addition to its endocrine action on skeletal muscle, cardiac myostatin production also modestly inhibits cardiomyocyte growth under certain circumstances, as well as induces cardiac fibrosis and alterations in ventricular function. Interestingly, heart failure patients show elevated myostatin levels in their serum. To therapeutically influence skeletal muscle wasting, direct inhibition of myostatin was shown to positively impact skeletal muscle mass in heart failure, suggesting a promising strategy for the treatment of cardiac cachexia in the future.

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Expression of Follistatin-Related Genes Is Altered in Heart Failure

Endocrinology ◽

10.1210/en.2008-0151 ◽

2008 ◽

Vol 149 (11) ◽

pp. 5822-5827 ◽

Cited By ~ 56

Author(s):

Enrique Lara-Pezzi ◽

Leanne E. Felkin ◽

Emma J. Birks ◽

Padmini Sarathchandra ◽

Kalyani D. Panse ◽

...

Keyword(s):

Heart Failure ◽

Disease Severity ◽

Calcium Binding ◽

Muscle Growth ◽

Left Ventricular ◽

Pharmacological Therapy ◽

Term Outcome ◽

Ventricular Assist ◽

Long Term Outcome ◽

Potential Link

Follistatins play roles in diverse biological processes including cell proliferation, wound healing, inflammation, and skeletal muscle growth, yet their role in the heart is currently unknown. We have investigated the myocardial expression profile and cellular distribution of follistatin (FST) and the FST-like genes FSTL1 and FSTL3 in the normal and failing heart. Expression was further analyzed in the novel setting of recovery from heart failure in myocardium obtained from patients who received combined mechanical (left ventricular assist device) and pharmacological therapy. Real-time PCR revealed that FSTL1 and FSTL3 expression was elevated in heart failure but returned to normal after recovery. FSTL3 expression levels correlated with molecular markers of disease severity and FSTL1 with the endothelial cell marker CD31, suggesting a potential link with vascularization. FSTL1 levels before treatment correlated with cardiac function after recovery, suggesting initial levels may influence long-term outcome. Immunohistochemistry revealed that FST was primarily localized to fibroblasts and vascular endothelium within the heart, whereas FSTL1 was localized to myocytes, endothelium, and smooth muscle cells and FSLT3 to myocytes and endothelium. Microarray analysis revealed that FST and FSTL1 were associated with extracellular matrix-related and calcium-binding proteins, whereas FSTL3 was associated mainly with cell signaling and transcription. These data show for the first time that elevated myocardial expression of FST-like genes is a feature of heart failure and may be linked to both disease severity and mechanisms underlying recovery, revealing new insight into the pathogenesis of heart failure and offering novel therapeutic targets.

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Abstract 1432: Cardiomyocyte Myostatin Contributes to Skeletal Muscle Wasting in Heart Failure

Circulation ◽

10.1161/circ.118.suppl_18.s_324-c ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Joerg Heineke ◽

Mannix Auger-Messier ◽

Michelle Sargent ◽

Allen York ◽

Stephen Welle ◽

...

Keyword(s):

Heart Failure ◽

Skeletal Muscle ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Muscle Wasting ◽

Muscle Growth ◽

Precursor Protein ◽

Mouse Serum ◽

Skeletal Muscle Growth ◽

Skeletal Muscle Wasting

Introduction: Skeletal muscle wasting during heart failure constitutes a major therapeutic challenge. The TGFβ superfamily member myostatin is a negative regulator of skeletal muscle growth. For example, elimination of myostatin (MSTN) in adult mice through an inducible Cre/lox recombination strategy has been shown to increase skeletal muscle mass by about 25%. Previous studies identified skeletal muscle and to a lesser extent cardiac and fat tissue as the source of MSTN production in the body. MSTN is produced as a precursor protein, which has been suggested to constitute the main reservoir of the protein in skeletal muscle. In mouse serum, however, MSTN is abundantly present in its mature form, which consists of the C-terminal fragment of the precursor protein. Results: We detected high levels of the mature MSTN protein (MM) in the mouse myocardium by western blotting. Interestingly, MM was significantly upregulated in the myocardium of mice subjected to long-term myocardial pressure overload (TAC, 12 weeks; protein levels: sham 100±22% vs. TAC 218±18%, p<0.01). In contrast, MM was barely detectable in mouse skeletal muscle. Immunhistochemical staining confirmed enhanced cardiomyocyte MSTN production after TAC. To determine the impact of cardiomyocyte MSTN on skeletal muscle growth during heart failure, we crossed cardiomyocyte specific Nkx2.5-Cre mice with mice in which the MSTN exon3 was flanked by loxp sites to eliminate expression of mature MSTN selectively in cardiomyocytes (CKO mice). While CKO mice did not have significant changes in skeletal muscle mass after a sham operation (e.g. quadriceps, normalized to tibia length: sham control 111±3.8 g/cm vs. sham CKO 106±4.3 g/cm), a 16% increase in skeletal muscle mass was observed in CKO mice after longterm TAC (quadriceps: TAC control 100±3.3 g/cm vs. TAC CKO 116±5.3 g/cm, p<0.05). In line with these results, mice with cardiomyocyte specific overexpression of MSTN (MSTN-Tg) showed a reduction in skeletal muscle mass (quadriceps: control 91±2.5 g/cm vs. MSTN-Tg 82±1.5 g/cm, p<0.05). Conclusion: Myocardial MSTN contributes to the development of skeletal muscle wasting in heart failure, most likely through an endocrine mechanism involving its secretion into the circulatory system.

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Mitochondria in Cardiomyopathy: Alterations in Size, Number and Internal Structures

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100100378 ◽

1968 ◽

Vol 26 ◽

pp. 126-127

Author(s):

George Hug ◽

William K. Schubert

Keyword(s):

Heart Failure ◽

Biochemical Analysis ◽

Left Ventricular ◽

Size Number ◽

Internal Structures ◽

Left Ventricular Outflow ◽

Chest X Ray ◽

Myocardial Fibers ◽

Muscle Biopsies ◽

Needle Liver Biopsy

A white boy six months of age was hospitalized with respiratory distress and congestive heart failure. Control of the heart failure was achieved but marked cardiomegaly, moderate hepatomegaly, and minimal muscular weakness persisted.At birth a chest x-ray had been taken because of rapid breathing and jaundice and showed the heart to be of normal size. Clinical studies included: EKG which showed biventricular hypertrophy, needle liver biopsy which showed toxic hepatitis, and cardiac catheterization which showed no obstruction to left ventricular outflow. Liver and muscle biopsies revealed no biochemical or histological evidence of type II glycogexiosis (Pompe's disease). At thoracotomy, 14 milligrams of left ventricular muscle were removed. Total phosphorylase activity in the biopsy specimen was normal by biochemical analysis as was the degree of phosphorylase activation. By light microscopy, vacuoles and fine granules were seen in practically all myocardial fibers. The fibers were not hypertrophic. The endocardium was not thickened excluding endocardial fibroelastosis. Based on these findings, the diagnosis of idiopathic non-obstructive cardiomyopathy was made.

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Localization of endothelial nitric oxide synthase in the normal and failing human atrial myocardium

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100166397 ◽

1996 ◽

Vol 54 ◽

pp. 786-787

Author(s):

Chi-Ming Wei ◽

Margarita Bracamonte ◽

Shi-Wen Jiang ◽

Richard C. Daly ◽

Christopher G.A. McGregor ◽

...

Keyword(s):

Nitric Oxide ◽

Heart Failure ◽

Nitric Oxide Synthase ◽

Endothelial Nitric Oxide Synthase ◽

Cardiac Tissues ◽

Mammalian Tissues ◽

End Stage Heart Failure ◽

End Stage ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Nitric oxide (NO) is a potent endothelium-derived relaxing factor which also may modulate cardiomyocyte inotropism and growth via increasing cGMP. While endothelial nitric oxide synthase (eNOS) isoforms have been detected in non-human mammalian tissues, expression and localization of eNOS in the normal and failing human myocardium are poorly defined. Therefore, the present study was designed to investigate eNOS in human cardiac tissues in the presence and absence of congestive heart failure (CHF).Normal and failing atrial tissue were obtained from six cardiac donors and six end-stage heart failure patients undergoing primary cardiac transplantation. ENOS protein expression and localization was investigated utilizing Western blot analysis and immunohistochemical staining with the polyclonal rabbit antibody to eNOS (Transduction Laboratories, Lexington, Kentucky).

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Expression of Concern: Normal-sodium diet compared with low-sodium diet in compensated congestive heart failure: is sodium an old enemy or a new friend?

Clinical Science ◽

10.1042/cs-20070193_eoc ◽

2020 ◽

Vol 134 (13) ◽

pp. 1841-1841

Keyword(s):

Heart Failure ◽

Congestive Heart Failure ◽

Sodium Diet ◽

Low Sodium Diet ◽

Low Sodium

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Protective role of peroxiredoxin-4 in heart failure

Clinical Science ◽

10.1042/cs20191072 ◽

2020 ◽

Vol 134 (1) ◽

pp. 71-72

Author(s):

Naseer Ahmed ◽

Masooma Naseem ◽

Javeria Farooq

Keyword(s):

Heart Failure ◽

Cardiac Fibroblasts ◽

Protective Role ◽

Oxidative Stress Markers ◽

Stress Markers ◽

Total Antioxidant ◽

Galectin 3 ◽

Consequent Increase ◽

And Oxidative Stress

Abstract Recently, we have read with great interest the article published by Ibarrola et al. (Clin. Sci. (Lond.) (2018) 132, 1471–1485), which used proteomics and immunodetection methods to show that Galectin-3 (Gal-3) down-regulated the antioxidant peroxiredoxin-4 (Prx-4) in cardiac fibroblasts. Authors concluded that ‘antioxidant activity of Prx-4 had been identified as a protein down-regulated by Gal-3. Moreover, Gal-3 induced a decrease in total antioxidant capacity which resulted in a consequent increase in peroxide levels and oxidative stress markers in cardiac fibroblasts.’ We would like to point out some results stated in the article that need further investigation and more detailed discussion to clarify certain factors involved in the protective role of Prx-4 in heart failure.

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