Impact of Cortisol on Reduction in Muscle Strength and Mass: A Mendelian Randomization Study
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Context: Prolonged exposure to pathological cortisol, as in Cushing’s syndrome causes various age-related disorders, including sarcopenia. However, it is unclear whether mild cortisol excess, for example, accelerates sarcopenia due to aging or chronic stress. Objective: We used Mendelian randomization (MR) analysis to assess whether cortisol was causally associated with muscle strength and mass. Methods: Three single-nucleotide polymorphisms associated with plasma cortisol concentrations in the CORtisol NETwork consortium (n = 12 597) were used as instrumental variables. Summary statistics with traits of interest were obtained from relevant genome-wide association studies. For the primary analysis, we used the fixed-effects inverse-variance weighted analysis accounting for genetic correlations between variants. Results: One SD increase in cortisol was associated with SD reduction in grip strength (estimate, −0.032; 95% CI −0.044 to −0.020; P = 3e-04), whole-body lean mass (estimate, −0.032; 95% CI, −0.046 to −0.017; P = 0.004), and appendicular lean mass (estimate, −0.031; 95% CI, −0.049 to −0.012; P = 0.001). The results were supported by the weighted-median analysis, with no evidence of pleiotropy in the MR-Egger analysis. The association of cortisol with grip strength and lean mass was observed in women but not in men. The association was attenuated after adjusting for fasting glucose in the multivariable MR analysis, which was the top mediator for the association in the MR Bayesian model averaging analysis. Conclusion: This MR study provides evidence for the association of cortisol with reduced muscle strength and mass, suggesting the impact of cortisol on the development of sarcopenia.
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Chronic stress elevates cortisol, which has catabolic effects on muscle tissue.
“Stress management is equally critical, as chronic stress elevates cortisol, a glucocorticoid hormone known to have catabolic effects on muscle tissue.”
From Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review (2024) · cites this paper as [90]
Elevated cortisol enhances muscle protein breakdown by promoting proteolysis, particularly in skeletal muscle, to mobilize amino acids for gluconeogenesis.
“Elevated cortisol levels enhance muscle protein breakdown by promoting proteolysis, particularly in skeletal muscle, to mobilize amino acids for gluconeogenesis in the liver.”
From Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review (2024) · cites this paper as [90]
Cortisol contributes to age-related sarcopenia by promoting protein degradation and inhibiting muscle synthesis, with elevated glucose possibly accelerating these effects.
“The findings suggest that cortisol contributes to age-related sarcopenia by promoting protein degradation and inhibiting muscle synthesis, with elevated glucose levels possibly accelerating these effects [90].”
From Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review (2024) · cites this paper as [90]
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BackgroundKilaitė, J., Pranckevičienė, E., Ginevičienė, V., Urnikytė, A., Dadelienė, R., Mastavičiūtė, A., Jamontaitė, I. E., Alekna, V., & Ahmetov, I. I. (2025) · Experimental Gerontology · doi:10.1016/j.exger.2025.112953 · Cited by 4 · see citing works
Tomaszewska, E., Wojtysiak, D., Grzegorzewska, A. K., Świątkiewicz, M., Donaldson, J., Arciszewski, M. B., Dresler, S., Puzio, I., Szymańczyk, S., Dobrowolski, P., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25168735 · Cited by 4 · see citing works
“The roles of cortisol and dysfunction of the HPA axis in the pathogenesis of SARC in aging individuals are well established [89,90].”
BackgroundPostoperative Stress, Metabolism, and Catabolism
Calvani, R., Picca, A., Coelho‐Júnior, H. J., Tosato, M., & Marzetti, E. (2024) · Practical issues in geriatrics · doi:10.1007/978-3-031-77707-3_21 · Cited by 3 · see citing works
Dimitriadis, M., Kokkeler, K. J. E., Hoogendijk, E. O., Marijnissen, R. M., Aprahamian, I., Jeuring, H. W., & Voshaar, R. C. O. (2026) · Age and Ageing · doi:10.1093/ageing/afag050 · Cited by 2 · see citing works
“Depression, in contrast, may represent a more proximal indicator of vulnerability to the physiological consequences of ACE, such as inflammation and HPA-axis dysregulation [5, 39], which could explain why it emerged as a significant moderator whereas demographic factors did not.”
Sarcopenia in cognitive disorders: Toward a shared pathophysiological framework
Liu, Y., Chua, K. H. C., Qi, C. G. Y., & Wang, J. D. J. (2026) · Osteoporosis and Sarcopenia · doi:10.1016/j.afos.2026.04.001 · Cited by 2 · see citing works
The relationship between temporal muscle thickness and disease activity in Cushing’s disease
Ozaydin, D., Demir, A. N., Öz, A., Birol, A., Sulu, C., Şahin, S., Arslan, Ş., Tanrıöver, N., Gazioğlu, N., & Kadıoğlu, P. (2023) · Journal of Endocrinological Investigation · doi:10.1007/s40618-023-02195-0 · Cited by 2 · see citing works
“demonstrated an inverse relationship between muscle mass and cortisol levels [34].”
BackgroundLeng, J., Zhou, T., Jiang, Y., Wang, B., Liu, S., Zhang, S., Li, L., & Zhao, W. (2024) · Food Science and Human Wellness · doi:10.26599/fshw.2024.9250333 · Cited by 1 · see citing works
Mutlu, Ü., Rasulova, N., Hacışahinoğulları, H., Yalın, G. Y., Gül, N., Üzüm, A. K., & Selçukbiricik, Ö. S. (2025) · Journal of Endocrinological Investigation · doi:10.1007/s40618-025-02668-4 · Cited by 1 · see citing works
Zhu, J.-Y., Zhou, S.-J., Jiang, M., Wang, W.-Y., & Yan, J. (2025) · Medicine · doi:10.1097/md.0000000000044153 · Cited by 2 · see citing works
Li, X., Xu, T., Zhou, L., Li, G., Yuan, Y., Song, H., Liu, C. X., & Liu, X. (2025) · Cancer Management and Research · doi:10.2147/cmar.s555236 · Cited by 1 · see citing works
Hu, Z., Sun, L., Peng, Y. H., Shi, J., Guo, Y., Fang, Q., Liu, C., Wei, X., Hong, J., Gu, W., et al. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1687909 · Cited by 1 · see citing works
“In accordance with the recent MR research concerning cortisol (29 – 31), we identi fi ed three single-nucleotide polymorphisms (SNPs) that were independently associated (r² 0.3) with morning cortisol levels at genome-wide signi fi cance (P 5*10 -8 ) (Supplementary Table S1).”
InfluentialChang, K. C., Wu, W., Chen, Y., Chen, L.-R., Lin, Y., & Han, D. (2025) · Journal of the International Society of Sports Nutrition · doi:10.1080/15502783.2025.2586555 · Cited by 1 · see citing works
“It has a mixed impact on muscle growth [12].”
Algabbani, M. F., abduljabbar, R., babtain, R., Alharthi, R., Alfaddaghi, S., Zuair, H. M. B., Alshehri, S. A., Alhammad, S. A., Abdelkader, S., Gawad, R. F. M., et al. (2025) · Work · doi:10.1177/10519815251406249 · Cited by 1 · see citing works
Zebrafish genetic model of neuromuscular degeneration associated with Atrogin-1 expression
Menard, R., Morin, E., Morse, D., Halluin, C., Pende, M., Baanannou, A., Grendler, J., Fuqua, J. H., Li, J., Lancelot, L., et al. (2026) · PLoS Genetics · doi:10.1371/journal.pgen.1012019 · Cited by 1 · see citing works
Clinical, laboratory and instrumental aspects of sarcopenia diagnostics
Станиславовна, Ж. А., Belaya, Z. E., Omelchenko, K. A., & Airapetov, G. A. (2026) · Osteoporosis and Bone Diseases · doi:10.14341/osteo13206 · Cited by 1 · see citing works
“Связь кортизола с силой захвата и мышечной мас-сой наблюдалась у женщин, но не у мужчин [38].”
Dong, C., Liu, S., Wu, L., Huoshen, W., Zhu, Y., & Luo, P. (2026) · iScience · doi:10.1016/j.isci.2026.115477 · Cited by 1 · see citing works
“24,25 These interpretations are hypothesis generating because the relevant mediators (e.g., access to mental health services, chronic stress burden, and social participation quality) are not uniformly measured across cohorts and, therefore, cannot be directly tested here.”
Romanisio, M., Mele, C., Sturnia, S., Ciamparini, C., Pitino, R., Ferrero, A., Scotti, L., Iftimie, M. E., Aimaretti, G., Marzullo, P., et al. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1803910 · Cited by 1 · see citing works
Molecular and metabolic effects of chronic stress on health, aging and carcinogenesis
Gerashchenko, G. V., & Tukalo, M. A. (2025) · Biopolymers and Cell · doi:10.7124/bc.000b0a · Cited by 1 · see citing works
Yoshida, Y., & Shibata, H. (2024) · Hypertension Research · doi:10.1038/s41440-024-02006-w · Cited by 1 · see citing works
“Although ACS alone is linked to higher visceral adipose tissue and reduced muscle quantity [9], the body composition of PA with and without ACS is unknown.”
Adams, N. N. (2025) · International Journal of Risk & Safety in Medicine · doi:10.1177/09246479251346445
“…which some have suggested may result from SSRI use, 40,41 could induce muscle catabolism, cortisol correlated negatively with lean muscle mass. 42 42 Such proposed mechanisms suggest that SSRI treatment may be able to contribute to muscle loss, warranting further investigation into the long-term…”
The Complexities of Metabolic Flexibility and Precision Approaches to Sustainable Weight Management
Theodorakis, N., Kreouzi, M., Pappas, A., Feretzakis, G., Sakagianni, A., Kalodanis, K., Αναστασίου, Α., Nikolaou, M., & Koumpouros, Y. (2025) · IGI Global eBooks · doi:10.4018/979-8-3693-5787-3.ch005
Zhai, X., & Yu, D. S. F. (2025) · Annals of Medicine · doi:10.1080/07853890.2025.2534085
“…characteristics influence psychological well-being, which in turn affects the risk of sarcopenia through both direct physiological mechanisms such as cortisol-related muscle breakdown [37], and indirect behavioral pathways such as reduced physical activity resulting from depression or anxiety [38].”
Arora, D., Pursnani, L., Mahapatra, H. S., Balakrishnan, M., Binoy, R., Sharma, L., K., H. P. M., Yadav, V., Dev, V., Lakshman, L., et al. (2025) · Research Square · doi:10.21203/rs.3.rs-7434137/v1
Liu, Y.-Q., Qi, F., Zhang, T., Pan, X., Li, M., & Song, Q. (2025) · BMC Geriatrics · doi:10.1186/s12877-025-06357-y
“Cortisol may inhibit protein synthesis via glucocorticoid receptors in skeletal tissue, leading to a reduction in muscle mass [48].”
Research Progress on Type 2 Diabetes with Sarcopenia and Glycemic Stability
孙, 静. (2025) · Journal of Clinical Personalized Medicine · doi:10.12677/jcpm.2025.46489
Impact of exam stress and time of day on hand grip fatigue in medical students
Giandonato, D., Rincon, N., Adamietz, N., & Mitov, M. I. (2026) · Scientific Reports · doi:10.1038/s41598-025-33886-8
“Previous research has suggested that high stress levels and elevated baseline cortisol concentrations may contribute to increased muscle fatigue and reduced muscle strength and mass 20,21 .”
Huang, L., Huang, Y., Chen, Y., Huang, Y., Yong, S., Zhou, C., Qian, B., Zhang, X., Li, S., Wang, Y., et al. (2026) · The journal of nutrition health & aging · doi:10.1016/j.jnha.2026.100911
“Additional intrinsic contributors include motor unit loss, selective atrophy of type II muscle fibers, and declines in anabolic hormones such as growth hormone and androgens [12].”
Computational precision nutrition for sarcopenia and associated multimorbidity in ageing.
Fu, G.-R., Chen, L.-Y., Wang, Z., & Fang, H. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103335
da Silva, C. B., Pimenta, I. T., Griep, R. H., Moreno, A. B., Benseñor, I. M., Barreto, S. M., Schmidt, M. I., Daliry, A., & da Fonseca, M. D. J. M. (2026) · Aging Medicine · doi:10.1002/agm2.70101
Differential Effects of Psychogenic Stress on Bone Morphology and Metabolism in Wistar Rats
Lee, S., Tatehana, H., Saito, T., Sugimoto, I., Kimura, Y., Kondo, I., & Itagaki, A. (2026) · Journal of Bone Metabolism · doi:10.11005/jbm.25.977
“PS activates the HPA axis, leading to increased cortisol secretion, which in turn upregulates receptor activator of nuclear factor-κB ligand (RANKL) and suppresses osteoprotegerin (OPG) expression levels.”
Yan, S., Wu, K., Han, W., Chang, L., Gu, Y., Kong, L., Wang, X., Wan, J., Sang, H., Yuan, H., et al. (2026) · Journal of Endocrinological Investigation · doi:10.1007/s40618-026-03045-5
- Authors
- Katsuhara, S., Yokomoto-Umakoshi, M., Umakoshi, H., Matsuda, Y., Iwahashi, N., Kaneko, H., Ogata, M., Fukumoto, T., Terada, E., Sakamoto, R., & Ogawa, Y.
- Affiliations
- Kyushu University (JP)
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Corresponding author
- Ogawa, Yoshihiro
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2021-11-28
- Volume
- 107
- Issue
- 4
- Pages
- e1477-e1487
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W3216395859
- Cited by
- 55
- References
- 59
- Citations by year
- 2026: 14 · 2025: 20 · 2024: 11 · 2023: 8 · 2022: 2
- FWCI
- 3.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Kyushu University Institutional Repository (QIR) (Kyushu University) (submittedVersion)
- Funders
- JSPS KAKENHI (21J40043, JP20K17514, JP20K17493)
- Daiwa Securities Health Foundation
- JSBMR Rising Stars
- JAPAN Osteoporosis Foundation
- Kaibara Morikazu Medical Science Promotion Foundation
- Japan Foundation for Applied Enzymology
- Qdai-jump Research Program
- Secom Science and Technology Foundation
- Topics
- Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
- Keywords
- cortisol, sarcopenia, muscle strength, lean body mass, grip strength, appendicular lean mass, chronic stress, aging, sex differences, fasting blood glucose, Cushing's syndrome, single nucleotide polymorphisms
- MeSH terms
- Bayes Theorem, Cushing Syndrome, Female, Humans, Hydrocortisone, Male, Hand Strength, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Sarcopenia, Mendelian Randomization Analysis
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