The DOI matches its Crossref record; 28 of the 28 references it cites were found in a registry or an index.
Genetic Deletion of Myostatin From the Heart Prevents Skeletal Muscle Atrophy in Heart Failure
Open accessAbstract
BACKGROUND: Cardiac cachexia is characterized by an exaggerated loss of skeletal muscle, weakness, and exercise intolerance, although the cause of these effects remains unknown. Here, we hypothesized that the heart functions as an endocrine organ in promoting systemic cachexia by secreting peptide factors such as myostatin. Myostatin is a cytokine of the transforming growth factor-beta superfamily that is known to control muscle wasting. METHODS AND RESULTS: We used a Cre/loxP system to ablate myostatin (Mstn gene) expression in a cell type-specific manner. As expected, elimination of Mstn selectively in skeletal muscle with a myosin light chain 1f (MLC1f)-cre allele induced robust hypertrophy in all skeletal muscle. However, heart-specific deletion of Mstn with an Nkx2.5-cre allele did not alter baseline heart size or secondarily affect skeletal muscle size, but the characteristic wasting and atrophy of skeletal muscle that typify heart failure were not observed in these heart-specific null mice, indicating that myocardial myostatin expression controls muscle atrophy in heart failure. Indeed, myostatin levels in the plasma were significantly increased in wild-type mice subjected to pressure overload-induced cardiac hypertrophy but not in Mstn heart-specific deleted mice. Moreover, cardiac-specific overexpression of myostatin, which increased circulating levels of myostatin by 3- to 4-fold, caused a reduction in weight of the quadriceps, gastrocnemius, soleus, and even the heart itself. Finally, to investigate myostatin as a potential therapeutic target for the treatment of muscle wasting in heart failure, we infused a myostatin blocking antibody (JA-16), which promoted greater maintenance of muscle mass in heart failure. CONCLUSIONS: Myostatin released from cardiomyocytes induces skeletal muscle wasting in heart failure. Targeted inhibition of myostatin in cardiac cachexia might be a therapeutic option in the future.
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“The importance of myostatin as an atrophic component is highlighted in patients with HF and cancer, who present increased serum levels of this protein, which can result in cachexia, which can only be reversed by the deletion of the gene, as can be observed in in vitro assays and transgenic animal models (George et al., 2010; Heineke et al., 2010).”
From Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases (2018) · cites this paper as Heineke et al., 2010
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Citations
Cites
Regulation of skeletal muscle mass in mice by a new TGF-p superfamily member
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Wasting as independent risk factor for mortality in chronic heart failure
Anker, S. D., Ponikowski, P. P., Varney, S. J., Chua, T. P., Clark, A. L., Webb-Peploe, K., Harrington, D., Kox, W. J., Poole-Wilson, P. A., & Coats, A. J. S. (1997) · The Lancet · doi:10.1016/s0140-6736(96)07015-8 · Cited by 1,399
Induction of Cachexia in Mice by Systemically Administered Myostatin
Zimmers, T. A., Davies, M. V., Koniaris, L. G., Haynes, P. A., Esquela‐Kerscher, A., Tomkinson, K. N., McPherron, A. C., Wolfman, N. M., & Lee, S. (2002) · Science · doi:10.1126/science.1069525 · Cited by 908
Functional improvement of dystrophic muscle by myostatin blockade
Bogdanovich, S., Krag, T. O. B., Barton, E. R., Morris, L. D., Whittemore, L.-A., Ahima, R. S., & Khurana, T. S. (2002) · Nature · doi:10.1038/nature01154 · Cited by 831
REGULATION OF MUSCLE MASS BY MYOSTATIN
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Calcineurin/NFAT Coupling Participates in Pathological, but not Physiological, Cardiac Hypertrophy
Wilkins, B. J., Dai, Y., Bueno, O. F., Parsons, S. A., Xu, J., Plank, D. M., Jones, F. S., Kimball, T. R., & Molkentin, J. D. (2003) · Circulation Research · doi:10.1161/01.res.0000109415.17511.18 · Cited by 762
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Cited by
Sorted by citations
Muscle wasting in disease: molecular mechanisms and promising therapies
Cohen, S., Nathan, J. A., & Goldberg, A. L. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4467 · Cited by 1,089
Reversal of Cancer Cachexia and Muscle Wasting by ActRIIB Antagonism Leads to Prolonged Survival
Zhou, X., Wang, J. L., Lu, J., Song, Y., Kwak, K. S., Jiao, Q., Rosenfeld, R., Chen, Q., Boone, T. C., Simonet, W. S., et al. (2010) · Cell · doi:10.1016/j.cell.2010.07.011 · Cited by 960
“It is noteworthy that myostatin and activin have been implicated in cardiac failure (Heineke et al., 2010; Rodgers et al., 2009; Springer et al., 2010; Yndestad et al., 2004).”
BackgroundTranscriptional mechanisms regulating skeletal muscle differentiation, growth and homeostasis
Braun, T., & Gautel, M. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3118 · Cited by 713
“The importance of myostatin as a negative regulator of muscle mass is highlighted by its increased serum levels in patients with heart failure, which leads to skeletal muscle cachexia that is completely blocked by genetic deletion of the gene encoding myostatin in heart tissu”
BackgroundMuscle type and fiber type specificity in muscle wasting
Ciciliot, S., Rossi, C. A., Dyar, K. A., Blaauw, B., & Schiaffino, S. (2013) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2013.05.016 · Cited by 644
Lenk, K., Schuler, G. C., & Adams, V. (2010) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1007/s13539-010-0007-1 · Cited by 498
“latter point is reinforced by a genetic deletion model of myostatin in HF, which was able to prevent muscle wasting.(141)”
Background
Metadata
- Authors
- Heineke, J., Auger-Messier, M., Xu, J., Sargent, M., York, A., Welle, S., & Molkentin, J. D.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- From the Department of Pediatrics, University of Cincinnati, Cincinnati Children’s Hospital Medical Center, Cincinnati (J.H., M.A.-M., J.X., M.S., A.Y., J.D.M.), and Department of Medicine, University of Rochester, School of Medicine and Dentistry, Rochester, NY (S.W.). Dr Heineke is currently at the Department of Cardiology and Angiology, Cluster of Excellence—Rebirth, Medizinische Hochschule Hannover, Hannover, Germany.
- Venue
- Circulation
- Published
- 2010-01-26
- Volume
- 121
- Issue
- 3
- Pages
- 419-425
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC2823256
- OpenAlex
- W2144331482
- Cited by
- 238
- References
- 28
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 14 · 2023: 11 · 2022: 18 · 2021: 14 · 2020: 11 · 2019: 12 · 2018: 14 · 2017: 16 · 2016: 23 · 2015: 21 · 2014: 10 · 2013: 12 · 2012: 21
- FWCI
- 7.69
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (P01HL069779, R37HL060562, R01HL062927)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Health Sciences › Medicine › Physiology (medical) › Nutrition and Health in Aging
- Keywords
- myostatin, heart failure, cardiac cachexia, skeletal muscle atrophy, heart as endocrine organ, cardiac hypertrophy, pressure overload
- MeSH terms
- Animals, Antibodies, Cachexia, Heart Failure, Mice, Inbred C57BL, Mice, Mutant Strains, Muscular Atrophy, Organ Specificity, Blotting, Western, Gene Expression, Muscle, Skeletal, Reverse Transcriptase Polymerase Chain Reaction, Myocytes, Cardiac, Mice, Myostatin, Gene Knock-In Techniques
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