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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Patients with heart failure and cancer present increased serum levels of myostatin, which can result in cachexia.
“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
The Results (page not provided) report a two- to threefold increase in circulating myostatin after heart-failure-inducing cardiac stress in mice, and the Discussion identifies cardiac myostatin as a mediator of muscle atrophy in that model. The paper does not establish increased serum myostatin in patients with heart failure or cancer, so the claim extends the mouse finding to populations the cited evidence does not cover. (LLM, conf=0.88)
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Increased Plasma Myostatin in Heart Failure
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de Souza, R. W. A., Piedade, W. P., Soares, L. C., Castro, P. A. T. D. S., Aguiar, A. F., Vechetti, I. J., de Campos, D. H. S., Fernandes, A. A. H., Okoshi, K., Carvalho, R. F., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0110020 · Cited by 104 · see citing works
“The transforming growth factor-b-related protein myostatin, a key regulator of muscle growth, has been considered an important mediator of cardiac-induced skeletal muscle wasting and cachexia in animal studies [5,60].”
BackgroundKnöll, R., Linke, W. A., Zou, P., Miočiċ, S., Sawa Kostin, D., Buyandelger, B., Ku, C.-H., Neef, S., Bug, M., Schäfer, K., et al. (2011) · Circulation Research · doi:10.1161/circresaha.111.245787 · Cited by 103 · see citing works
Alcoholic Myopathy: Pathophysiologic Mechanisms and Clinical Implications
Simon, L. (2017) · Alcohol research · doi:10.35946/arcr.v38.2.05 · Cited by 102 · see citing works
“Alcoholic Myopathy: Pathophysiologic Mechanisms and Clinical Implications | 215 can inhibit myostatin function (i.e., myostatin antagonists) in heart failure and sarcopenia models resulted in a reduction in Smad signaling, preventing loss of muscle mass (Heineke et al. 2010; Murphy et al. 2011).”
Myostatin Regulates Energy Homeostasis in the Heart and Prevents Heart Failure
Biesemann, N., Mendler, L., Wietelmann, A., Hermann, S., Schäfers, M. A., Krüger, M., Boettger, T., Borchardt, T., & Braun, T. W. (2014) · Circulation Research · doi:10.1161/circresaha.115.304185 · Cited by 101 · see citing works
Prevalence and Mechanisms of Skeletal Muscle Atrophy in Metabolic Conditions
Jun, L., Robinson, M., Geetha, T., Broderick, T. L., & Babu, J. R. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032973 · Cited by 101 · see citing works
“Indeed, upregulation of plasma myostatin is reported in patients with HF, and inhibiting myostatin in cardiac cachectic mice promoted greater maintenance of muscle mass [184].”
BackgroundInfluential<i>Smad7</i> gene delivery prevents muscle wasting associated with cancer cachexia in mice
Winbanks, C. E., Murphy, K. T., Bernardo, B. C., Qian, H., Liu, Y., Sepulveda, P. V., Beyer, C., Hagg, A., Thomson, R. E., Chen, J. L., et al. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aac4976 · Cited by 95 · see citing works
“Increased expression of myostatin and activin A is associated with heart disease (30, 41, 42), whereas conversely, physiological cardiac hypertrophy, enhanced cardiac contractility, and protection from cardiac atrophy occur in myostatinnull mice and cardiac muscle (42–45).”
BackgroundMyostatin Up-Regulation Is Associated with the Skeletal Muscle Response to Hypoxic Stimuli
Hayot, M., Rodriguez, J., Vernus, B., Carnac, G., Jean, E., Allen, D., Goret, L., Obert, P., Candau, R., & Bonnieu, A. (2011) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2010.09.008 · Cited by 98 · see citing works
Mueller, T. C., Bachmann, J., Prokopchuk, O., Friess, H., & Martignoni, M. E. (2016) · BMC Cancer · doi:10.1186/s12885-016-2121-8 · Cited by 95 · see citing works
“Furthermore, mice with a heart-specific knockout of the myostatin gene appear to be resistant to skeletal muscle loss, which indicates that targeting this pathway could be of benefit for patients with muscle wasting in the context of chronic heart failure and maybe also in cancer cachexia [183, 184].”
BackgroundTargeting the myostatin signaling pathway to treat muscle wasting diseases
Han, H. Q., & Mitch, W. E. (2011) · Current Opinion in Supportive and Palliative Care · doi:10.1097/spc.0b013e32834bddf9 · Cited by 92 · see citing works
Silencing Myostatin Using Cholesterol-conjugated siRNAs Induces Muscle Growth
Khan, T., Weber, H., DiMuzio, J. M., Matter, A. M., Dogdas, B., Shah, T., Thankappan, A., Disa, J., Jadhav, V., Lubbers, L. S., et al. (2016) · Molecular Therapy — Nucleic Acids · doi:10.1038/mtna.2016.55 · Cited by 90 · see citing works
Cancer-induced cardiac cachexia: Pathogenesis and impact of physical activity
Belloum, Y., Rannou‐Bekono, F., & Favier, F. B. (2017) · Oncology Reports · doi:10.3892/or.2017.5542 · Cited by 90 · see citing works
“However, cardiac-specific myostatin deletion did not restore either heart mass or function in a model of HF in mice (62).”
BackgroundGeng, T., Li, P., Yin, X., & Yan, Z. (2011) · American Journal Of Pathology · doi:10.1016/j.ajpath.2011.01.005 · Cited by 90 · see citing works
Myostatin is a key mediator between energy metabolism and endurance capacity of skeletal muscle
Mouisel, É., Relizani, K., Mille-Hamard, L., Denis, R., Hourdé, C., Agbulut, O., Patel, K., Arandel, L., Morales-Gonzalez, S., Vignaud, A., et al. (2014) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00377.2013 · Cited by 89 · see citing works
“, in sarcopenia, cardiac cachexia, and tumor cachexia) might outweigh the negative effect on muscle metabolism by far (19, 27, 49).”
BackgroundExercise intolerance in heart failure with preserved ejection fraction: more than a heart problem.
Upadhya, B., Haykowsky, M. J., Eggebeen, J., & Kitzman, D. W. (2015) · Europe PMC (PubMed Central) · doi:10.11909/j.issn.1671-5411.2015.03.013 · Cited by 98 · see citing works
Metabolic and structural impairment of skeletal muscle in heart failure
Zizola, C. F., & Schulze, P. C. (2012) · Heart Failure Reviews · doi:10.1007/s10741-012-9353-8 · Cited by 88 · see citing works
“Several authors have suggested a role of myostatin in muscle atrophy in patients with advanced HF [65].”
BackgroundSarcopenia in heart failure: mechanisms and therapeutic strategies.
Collamati, A., Marzetti, E., Calvani, R., Tosato, M., D’Angelo, E., Sisto, A. N., & Landi, F. (2016) · PubMed Central · doi:10.11909/j.issn.1671-5411.2016.07.004 · Cited by 88 · see citing works
Skeletal muscle derived Musclin protects the heart during pathological overload
Szaroszyk, M., Kattih, B., Martín-Garrido, A., Trogisch, F. A., Dittrich, G. M., Grund, A., Abouissa, A., Derlin, K., Meier, M., Holler, T., et al. (2022) · Nature Communications · doi:10.1038/s41467-021-27634-5 · Cited by 86 · see citing works
“While it is known that the heart secretes factors under pathological conditions to trigger skeletal muscle wasting by endocrine inter-tissue crosstalk 9 – 11 , the mechanisms how skeletal muscle wasting aggravates heart failure in the course of cardiac cachexia remains unclear.”
Myostatin: a skeletal muscle chalone
Lee, S.-J. (2023) · Annual Review of Physiology · doi:10.1146/annurev-physiol-012422-112116 · Cited by 84 · see citing works
Metabolism and the heart: An overview of muscle, fat, and bone metabolism in heart failure
Loncar, G., Fülster, S., von Haehling, S., & POPOVIC, V. M. (2011) · International Journal of Cardiology · doi:10.1016/j.ijcard.2011.09.079 · Cited by 84 · see citing works
Impact of exercise training on cardiovascular disease and risk
Adams, V., & Linke, A. H.-P. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2018.08.019 · Cited by 85 · see citing works
Abati, E., Manini, A., Comi, G. P., & Corti, S. P. (2022) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-022-04408-w · Cited by 83 · see citing works
Upadhya, B., Haykowsky, M. J., Eggebeen, J., & Kitzman, D. W. (2015) · Current Heart Failure Reports · doi:10.1007/s11897-015-0257-5 · Cited by 79 · see citing works
Harper (2016) · doi:10.1161/circresaha.116.307962 · Cited by 74 · see citing works
Muscle Atrophy: Present and Future
Cao, R. Y., Li, J., Dai, Q., Li, Q. X., & Yang, J. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-1435-3_29 · Cited by 75 · see citing works
Myostatin: Basic biology to clinical application
Esposito, P. B., Picciotto, D., Battaglia, Y., Costigliolo, F., Viazzi, F. C., & Verzola, D. (2022) · Advances in clinical chemistry · doi:10.1016/bs.acc.2021.09.006 · Cited by 70 · see citing works
SMAD3 augments FoxO3-induced MuRF-1 promoter activity in a DNA-binding-dependent manner
Bollinger, L. M., Witczak, C. A., Houmard, J. A., & Brault, J. J. (2014) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00391.2013 · Cited by 65 · see citing works
Jackson, M. F., Luong, D., Vang, D. D., Garikipati, D. K., Stanton, J. B., Nelson, O. L., & Rodgers, B. D. (2012) · Journal of Endocrinology · doi:10.1530/joe-11-0455 · Cited by 64 · see citing works
“It is surprising, therefore, that some studies have failed to identify cardiac hypertrophy in MstnK/K mice (Morissette et al. 2006, Cohn et al. 2007, Heineke et al. 2010) especially as overexpressing myostatin stimulates cardiac Journal of Endocrinology (2012) 213, 263–275 atrophy (Artaza et al.…”
ResultHulmi, J., Nissinen, T., Räsänen, M., Degerman, J., Lautaoja, J. H., Hemanthakumar, K. A., Backman, J., Ritvos, O., Silvennoinen, M., & Kivelä, R. (2017) · Journal of Cachexia, Sarcopenia and Muscle · doi:10.1002/jcsm.12265 · Cited by 55 · see citing works
“Myostatin inhibition has had variable effects on heart size depending on the model used.(18,25,63) Based on recent evidence, GDF11 that has high homology with myostatin, and is also a ligand for ACVR2B, may be more potent in inducing cardiac atrophy than myostatin.”
BackgroundMethodConraads, V. M., Craenenbroeck, E. M. V., Maeyer, C. D., Berendoncks, A. M. V., Beckers, P. J., & Vrints, C. J. (2012) · Heart Failure Reviews · doi:10.1007/s10741-012-9324-0 · Cited by 61 · see citing works
“, after transverse aortic banding [84] and LAD ligation [85]) and is clearly related to muscle wasting.”
BackgroundFinding good biomarkers for sarcopenia
Scharf, G. M., & Heineke, J. (2012) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1007/s13539-012-0081-7 · Cited by 59 · see citing works
“Importantly, myostatin is present in serum, and local overexpression of myostatin as well as peripheral myostatin overexpression (for example, in the heart) in mice leads to a dramatic reduction in skeletal muscle mass [21, 22].”
BackgroundTaking pressure off the heart: the ins and outs of atrophic remodelling
Baskin, K. K., & Taegtmeyer, H. (2011) · Cardiovascular Research · doi:10.1093/cvr/cvr060 · Cited by 60 · see citing works
Myostatin — From the Mighty Mouse to cardiovascular disease and cachexia
Dschietzig, T. B. (2014) · Clinica Chimica Acta · doi:10.1016/j.cca.2014.03.021 · Cited by 55 · see citing works
Cai, M., Wang, Q., Liu, Z., Jia, D., Feng, R., & Tian, Z. (2018) · Life Sciences · doi:10.1016/j.lfs.2018.10.015 · Cited by 53 · see citing works
“Previous studies demonstrated that MSTN expression modulated oxidative stress in skeletal muscle [72], and up-regulation of MSTN expression in skeletal muscle after MI may be one of the main factors of skeletal muscle atrophy [73].”
BackgroundCastillero, E., Akashi, H., Wang, C. K., Najjar, M., Ji, R., Kennel, P. J., Sweeney, H. L., Schulze, P. C., & George, I. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.12.057 · Cited by 52 · see citing works
“[12], together with our results show the importance of cardiac factors on skeletal muscle tropism.”
BackgroundResultInfluentialPalus, S., von Haehling, S., FLACH, V., Tschirner, A., Doehner, W., Anker, S. D., & Springer, J. (2013) · International Journal of Cardiology · doi:10.1016/j.ijcard.2013.04.150 · Cited by 51 · see citing works
Skeletal muscle atrophy, regeneration, and dysfunction in heart failure: Impact of exercise training
Gallagher, H., Hendrickse, P. W., Pereira, M. G., & Bowen, T. S. (2023) · Journal of sport and health science/Journal of Sport and Health Science · doi:10.1016/j.jshs.2023.04.001 · Cited by 53 · see citing works
Treating cancer cachexia to treat cancer
Lee, S., & Glass, D. J. (2011) · Skeletal Muscle · doi:10.1186/2044-5040-1-2 · Cited by 49 · see citing works
“Importantly, mice carrying a heart-specific knockout of the Mstn gene appear to be resistant to skeletal muscle loss following transverse aortic constriction [30].”
BackgroundVerzola, D., Milanesi, S., Bertolotto, M. B., Garibaldi, S., Villaggio, B., Brunelli, C., Balbi, M., Ameri, P., Montecucco, F., Palombo, D., et al. (2017) · Scientific Reports · doi:10.1038/srep46362 · Cited by 52 · see citing works
Significance of Sarcopenia Evaluation in Acute Decompensated Heart Failure
Tsuchida, K., Fujihara, Y., Hiroki, J., Hakamata, T., Sakai, R., Nishida, K., Sudo, K., Tanaka, K., Hosaka, Y., Takahashi, K., et al. (2018) · International Heart Journal · doi:10.1536/ihj.17-057 · Cited by 50 · see citing works
Sarcopenia and Frailty in Heart Failure: Is There a Biomarker Signature?
Sato, R., Vatic, M., da Fonseca, G. W. P., & von Haehling, S. (2022) · Current Heart Failure Reports · doi:10.1007/s11897-022-00575-w · Cited by 49 · see citing works
The histone deacetylase SIRT6 blocks myostatin expression and development of muscle atrophy
Samant, S. A., Kanwal, A., Pillai, V. B., Bao, R., & Gupta, M. P. (2017) · Scientific Reports · doi:10.1038/s41598-017-10838-5 · Cited by 46 · see citing works
Okada, K., Naito, A. T., Higo, T., Nakagawa, A., Shibamoto, M., Sakai, T., Hashimoto, A., Kuramoto, Y., Sumida, T. S., Nomura, S., et al. (2015) · Circulation Heart Failure · doi:10.1161/circheartfailure.114.001958 · Cited by 45 · see citing works
“However, we did not observe skeletal muscle wasting in this study, in part because of the differences in the animal models.(10,26) The fiber type shift toward fatigable fiber is another major abnormality in CHF-associated skeletal myopathy and accounts for the exercise intolerance in patients with CHF.”
BackgroundCall, J. A., Chain, K. H., Martin, K. S., Lira, V. A., Okutsu, M., Zhang, M., & Yan, Z. (2014) · Circulation Heart Failure · doi:10.1161/circheartfailure.114.001540 · Cited by 45 · see citing works
Shimano, M., Ouchi, N., Nakamura, K., Oshima, Y., Higuchi, A., Pimentel, D. R., Panse, K. D., Lara‐Pezzi, E., Lee, S., Sam, F., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.197079 · Cited by 45 · see citing works
Advances in sarcopenia: mechanisms, therapeutic targets, and intervention strategies
Zheng, Y., Feng, J., Yu, Y., Ling, M., & Wang, X. (2024) · Archives of Pharmacal Research · doi:10.1007/s12272-024-01493-2 · Cited by 45 · see citing works
“Encouragingly, the administration of JA-16 showed promising results by effectively preserving muscle mass in individuals with heart failure (Heineke et al. 2010).”
Skeletal Muscle Abnormalities in Chronic Heart Failure
Γεωργιάδου, Π., & Adamopoulos, S. N. (2012) · Current Heart Failure Reports · doi:10.1007/s11897-012-0090-z · Cited by 44 · see citing works
Cho, J., Choi, Y., Sajgalik, P., No, M., Lee, S.-H., Kim, S., Heo, J., Cho, E., Chang, E., Kang, J., et al. (2020) · Cells · doi:10.3390/cells9102284 · Cited by 44 · see citing works
“Deletion of the myostatin gene in heart tissues prevented skeletal muscle atrophy in animal HF models [87].”
BackgroundThe regulation of muscle protein turnover in diabetes
Workeneh, B., & Bajaj, M. (2013) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2013.06.028 · Cited by 43 · see citing works
Lamar, K., Bogdanovich, S., Gardner, B. B., Gao, Q. Q., Miller, T. A., Earley, J. U., Hadhazy, M., Vo, A. H., Wren, L. M., Molkentin, J. D., et al. (2016) · PLoS Genetics · doi:10.1371/journal.pgen.1006019 · Cited by 43 · see citing works
The Role of TGF—β Signaling in Cardiomyocyte Proliferation
Sorensen, D. W., & van Berlo, J. H. (2020) · Current Heart Failure Reports · doi:10.1007/s11897-020-00470-2 · Cited by 42 · see citing works
Bosco, F., Musolino, V., Gliozzi, M., Nucera, S., Carresi, C., Zito, M. C., Scarano, F., Scicchitano, M., Reale, F., Ruga, S., et al. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105427 · Cited by 45 · see citing works
- 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 › 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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