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Growth and differentiation factor 15 is secreted by skeletal muscle during exercise and promotes lipolysis in humans
Open accessAbstract
We hypothesized that skeletal muscle contraction produces a cellular stress signal, triggering adipose tissue lipolysis to sustain fuel availability during exercise. The present study aimed at identifying exercise-regulated myokines, also known as exerkines, able to promote lipolysis. Human primary myotubes from lean healthy volunteers were submitted to electrical pulse stimulation (EPS) to mimic either acute intense or chronic moderate exercise. Conditioned media (CM) experiments with human adipocytes were performed. CM and human plasma samples were analyzed using unbiased proteomic screening and/or ELISA. Real-time qPCR was performed in cultured myotubes and muscle biopsy samples. CM from both acute intense and chronic moderate exercise increased basal lipolysis in human adipocytes. Growth and differentiation factor 15 (GDF15) gene expression and secretion increased rapidly upon skeletal muscle contraction. GDF15 protein was upregulated in CM from both acute and chronic exercise–stimulated myotubes. We further showed that physiological concentrations of recombinant GDF15 protein increased lipolysis in human adipose tissue, while blocking GDF15 with a neutralizing antibody abrogated EPS CM-mediated lipolysis. We herein provide the first evidence to our knowledge that GDF15 is a potentially novel exerkine produced by skeletal muscle contraction and able to target human adipose tissue to promote lipolysis.
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“acute exercise in humans also releases additional molecules79, such as growth and differentiation factor 15 (GDF15)80 and IL-6 (REF.81), which also affect lipolysis”
From Exerkines in health, resilience and disease (2022) · cites this paper as [80]
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InfluentialExercise-Mediated Browning of White Adipose Tissue: Its Significance, Mechanism and Effectiveness
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BackgroundBrown Fat–Activating Lipokine 12,13-diHOME in Human Milk Is Associated With Infant Adiposity
Wolfs, D., Lynes, M. D., Tseng, Y., Pierce, S., Bussberg, V., Darkwah, A., Tolstikov, V., Narain, N. R., Rudolph, M. C., Kiebish, M. A., et al. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa799 · Cited by 60
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Plomgaard, P., Hansen, J. S., Townsend, L. K., Gudiksen, A., Secher, N. H., Clemmesen, J. O., Støving, R. K., Goetze, J. P., Wright, D. C., & Pilegaard, H. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.1037948 · Cited by 43
“Cultured muscle cells exposed to electrical pulse stimulation secrete GDF15 to the medium (30), and despite a low expression in the skeletal muscles, exercise induces a transient increase in muscle GDF15 mRNA in mice (31).”
BackgroundGFRAL Is Widely Distributed in the Brain and Peripheral Tissues of Mice
Fichtner, K., Kalwa, H., Lin, M., Gong, Y., Müglitz, A., Kluge, M., & Krügel, U. (2024) · Nutrients · doi:10.3390/nu16050734 · Cited by 39
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Aguilar-Recarte, D., Palomer, X., Wahli, W., & Vázquez‐Carrera, M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22168555 · Cited by 40
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Townsend, L. K., MacPherson, R. E. K., & Wright, D. C. (2021) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgab333 · Cited by 36
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Altered GDF15 and FGF21 Levels in Response to Strenuous Exercise: A Study in Marathon Runners
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“The negative association between 294 change in plasma GDF15 and change in BMI during the LCD was previously reported (32), but no 295”
BackgroundSelf-citationExercise-regulated lipolysis: Its role and mechanism in health and diseases
Zhu, J., & Guo, L. (2024) · Journal of Advanced Research · doi:10.1016/j.jare.2024.11.031 · Cited by 33
“After conditioned media culture, it was found that the culture media of exercise-stimulated myotubes led to higher levels of FFAs and glycerol released from human adipocytes while blocking GDF15 with a neutralizing antibody blunted this effect [38].”
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“Examples of myokines that have been shown to influence adipocyte function include IL-6 and growth and differentiation factor 15 (GDF15) (46, 47).”
Discovery of thymosin β4 as a human exerkine and growth factor
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“It has also been demonstrated that GDF15 increases in response to physical exertion, where it is produced by muscles [27].”
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“The highest expression of GFRAL has been detected in neurons of brainstem area postrema and nucleus of the solitary tract in mice and humans [27], but its presence has also been confirmed in human adipose tissue [29].”
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“The skeletal muscle tissue is a possible source, stimulated to produce GDF-15 by muscle contraction [120].”
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“However, other studies addressing the promotion of weight loss in obese adults and/or elderly individuals have reported that a lifestyle-modifying intervention combining exercise and diet restriction increased the levels of circulating GDF15 [59,60].”
BackgroundNutritional Mechanisms of Cancer Cachexia
Compton, S. L. E., Heymsfield, S. B., & Brown, J. C. (2024) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-062122-015646 · Cited by 23
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“However, it is unclear if these effects are mediated by the GFRAL receptor [99].”
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“Furthermore, elevated GDF15 has been linked to the activation of the hypothalamic–pituitary–adrenal axis, resulting in increased corticosterone levels and enhanced fatty acid oxidation in the liver, which is consistent with GDF15’s role in promoting lipolysis 123,124 .”
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“Exercise-induced mitochondrial stress increases skeletal muscle expression levels of both factors, 74,176 and these mitokines are released into the systemic circulation to stimulate adipose tissue thermogenesis, lipolysis, and fatty acid oxidation, leading to the alleviation of obesity and…”
BackgroundDistinct roles of UVRAG and EGFR signaling in skeletal muscle homeostasis
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“Gdf15 has been suggested as a marker of muscle wasting after cardiovascular surgery [46,47], is secreted by skeletal muscle during exercise, and promotes lipolysis [48].”
BackgroundExercise/Resistance Training and Muscle Stem Cells
Fukada, S., & Nakamura, A. (2021) · Endocrinology and Metabolism · doi:10.3803/enm.2021.401 · Cited by 20
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“Recent data showed that GFRAL expression is also present in human adipocytes and prostate cancer cells (29, 30).”
BackgroundMyokines: Novel therapeutic targets for diabetic nephropathy
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“Moreover, electrical stimulation induced the contraction of primary human muscle cells for 3 h and also induced the release of GDF15 into the culture medium (112).”
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Endocrine Mechanisms Connecting Exercise to Brown Adipose Tissue Metabolism: a Human Perspective
Méndez-Gutiérrez, A., Osuna‐Prieto, F. J., Aguilera, C. M., Ruiz, J. R., & Sánchez‐Delgado, G. (2020) · Current Diabetes Reports · doi:10.1007/s11892-020-01319-7 · Cited by 17
“liver, it is also expressed, among others, in the skeletal muscle, WAT, and BAT [46, 47].”
BackgroundRegulation of diurnal energy balance by mitokines
Klaus, S., Gil, C. I., & Ost, M. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03748-9 · Cited by 19
CHOP is dispensable for exercise-induced increases in GDF15
Townsend, L. K., Medak, K. D., Weber, A. J., Dibe, H. A., Shamshoum, H., & Wright, D. C. (2021) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00698.2021 · Cited by 17
Aerobic exercise and lipolysis: A review of the β-adrenergic signaling pathways in adipose tissue
Rodrigues, A. C., Prímola‐Gomes, T. N., Pelúzio, M. D. C. G., Hermsdorff, H. H. M., & Natali, A. J. (2020) · Science & Sports · doi:10.1016/j.scispo.2020.04.006 · Cited by 16
Mimicking exercise in vitro: effects of myotube contractions and mechanical stretch on omics
Lautaoja-Kivipelto, J. H., Turner, D. C., Sharples, A. P., Kivelä, R., Pekkala, S., Hulmi, J. J., & Ylä‐Outinen, L. (2023) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00586.2022 · Cited by 15
Fiorenza, M., Checa, A., Sandsdal, R. M., Jensen, S. B. K., Juhl, C. R., Noer, M. H., Bogh, N. P., Lundgren, J. R., Janus, C., Stallknecht, B. M., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101629 · Cited by 14
“11,12 15–17 Expression of FGF21 and GDF15 is regulated by the same molecular pathway, namely the integrated stress response, which is activated by a variety of cellular stresses.”
Poor Appetite & Aging: The Role of Physical Activity under a Geroscience Perspective
Barreto, P. D. S. (2022) · The journal of nutrition health & aging · doi:10.1007/s12603-022-1849-x · Cited by 14
“GDF15 may be considered as an exerkine, since it is secreted by the muscle during exercise (23).”
BackgroundThe search for systemic biomarkers for monitoring degenerative lumbar spinal disorders
Tarabeih, N., Shalata, A., Higla, O., Kalinkovich, A., & Livshits, G. (2022) · Osteoarthritis and Cartilage Open · doi:10.1016/j.ocarto.2022.100323 · Cited by 13
Huang, Q., Monzel, A. S., Rausser, S., Haahr, R., Indik, C. E., Savin, M. J., Bobba‐Alves, N., Liu, C. C., Devine, J., Thompson, E., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.04.19.590241 · Cited by 16
Cancer cachexia: A tumor-driven disorder of whole-body homeostasis
Zhang, Y., Nipp, R. D., Janowitz, T., Li, Y.-P., Guttridge, D. C., & Li, M. (2026) · Cancer Cell · doi:10.1016/j.ccell.2026.03.012 · Cited by 16
“29–31 Many systemic effects are mediated through the canonical GFRAL pathway, linking central appetite regulation to whole-body metabolic adaptation.”
The different effects of intramuscularly-injected lactate on white and brown adipose tissue in vivo
Qu, Y., Chen, S., Zhou, L., Chen, M., Li, L., Ni, Y., & Sun, J. (2022) · Molecular Biology Reports · doi:10.1007/s11033-022-07672-y · Cited by 12
“Exercise ameliorates metabolic health, promotes lipolysis, and prevents the complications of obesity and type 2 diabetes [1, 2].”
BackgroundGDF15 mediates renal cell plasticity in response to potassium depletion in mice
Lasaad, S., Walter, C., Rafael, C., Morla, L., Doucet, A., Picard, N., Blanchard, A., Fromes, Y., Matot, B., Crambert, G., et al. (2023) · Acta Physiologica · doi:10.1111/apha.14046 · Cited by 13
Genome-wide analysis of a cellular exercise model based on electrical pulse stimulation
Lee, B., Kim, S., Shin, Y. J., Son, Y. H., Yang, J. W., Lee, S.-M., Yang, Y. R., Lee, K., & Kwon, K. (2022) · Scientific Reports · doi:10.1038/s41598-022-25758-2 · Cited by 12
“Studies involving organ-to-muscle communication by co-culturing muscle cells with other cell types 55 and using EPS-conditioned medium 56–58 have been conducted to address these differences.”
Katz, D. H., Lindholm, M. E., & Ashley, E. A. (2024) · Physiology · doi:10.1152/physiol.00024.2024 · Cited by 12
Abubaker, J. A., Abu‐Farha, M., Albatineh, A. N., Al‐Khairi, I., Cherian, P., Ali, H., Taher, I., Alajmi, F., Qaddoumi, M., Abdul‐Ghani, M. A., et al. (2025) · Biomedicines · doi:10.3390/biomedicines13071589 · Cited by 10
“A similar effect has been observed with high-and moderate-intensity exercise [21,22].”
Jachim, S. K., Sakamoto, A. E., Zhang, X., Pearsall, V. M., Schafer, M. J., & LeBrasseur, N. K. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101147 · Cited by 12
“, 2019), GDF15 (Conte et al., 2020; Laurens et al., 2020), GPLD1 (Horowitz et al.”
InfluentialWen, B., Tang, R., Tang, S., Sun, Y., Xu, J., Zhao, D., Wang, T., & Yan, C. (2024) · Journal of Human Genetics · doi:10.1038/s10038-023-01216-3 · Cited by 9
Nintou, E., Karligiotou, E., Vliora, M., Ioannou, L. G., & Flouris, A. D. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232113446 · Cited by 9
“Published studies have used electrical pulse stimulation to induce acute [16–19] and chronic [20,21] exercise; aerobic [22], endurance [19,23], and resistance training [24]; and high-intensity [25] and moderate activity [26].”
BackgroundInfluentialRelevance of GDF15 as a biomarker for clinical outcomes after bariatric surgery
Urones, P., Juiz-Valiña, P., Outeiriño-Blanco, E., García-Brao, M. J., Barreiro, V. B., Cordido, F., & Sangiao‐Alvarellos, S. (2025) · Journal of Endocrinology · doi:10.1530/joe-25-0010 · Cited by 9
The role of GDF15 in food intake and appetitive behaviour
Cimino, I., & Coll, A. P. (2021) · Current Opinion in Endocrine and Metabolic Research · doi:10.1016/j.coemr.2021.100299 · Cited by 8
GDF15 is dispensable for the insulin-sensitizing effects of chronic exercise
Labour, A., Lac, M., Frassin, L., Lair, B., Murphy, E. E., Maslo, C., Monbrun, L., Calmy, M.-L., Marqués, M.-A., Viguerie, N., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114577 · Cited by 9
Self-citationGDF15 is required for maintaining subcutaneous adipose tissue lipid metabolic signature
Igual-Gil, C., Bishop, C. A., Jähnert, M., Johann, K., Coleman, V., Baum, V., Kruse, M., Pfeiffer, A. F. H., Pivovarova‐Ramich, O., Ost, M., et al. (2024) · Scientific Reports · doi:10.1038/s41598-024-77448-w · Cited by 8
Rao, Z., Geng, X. H., Huang, P., Wei, Q., Liu, S., Qu, C., & Zhao, J. (2024) · Experimental Physiology · doi:10.1113/ep092319 · Cited by 6
“A recent study reported that GDF15 increased rapidly in response to muscle contraction (Laurens et al., 2020).”
Skeletal muscle growth to combat diabetes and obesity: the potential role of muscle‐secreted factors
Sammut, M. J., Thorne, B. R., & Melling, C. W. J. (2025) · Obesity · doi:10.1002/oby.24223 · Cited by 8
“Furthermore, the GDF15-rich conditioned media collected from contracting SkM cells increases lipolysis in adipocytes via GDNF family receptor α -like (GFRAL)/rearranged during transfection (RET) receptors, which was prevented following treatment with anti-GDF15 antibodies [45].”
Growth differentiation factor 15 as a potential diagnostic biomarker for rheumatoid arthritis
Liu, X., Essien, A. E., Lu, W., Jin, H., Pan, L., Li, Y., & Xiao, W. (2025) · Bone and Joint Research · doi:10.1302/2046-3758.145.bjr-2024-0230.r2 · Cited by 6
“40,44 For instance, Wang et al 45 reported increased serum GDF-15 in patients with cardiovascular disease, indicating its potential utility in detecting myocardial infarction and predicting mortality.”
Exerkines: Benign adaptation for exercise and benefits for non-alcoholic fatty liver disease
Chen, Y., Zhang, Y., Jin, X., Hong, S., & Tian, H. (2024) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2024.150305 · Cited by 5
Pancreatic cancer cachexia: A systemic consequence of multi-organ interactions
Xiao, A., Feng, Y., Yin, B., Zhang, J., Cao, Z., Liu, X., Liang, Y., & Wu, W. (2025) · hLife · doi:10.1016/j.hlife.2025.05.002 · Cited by 6
Exercise as elixir to combat cardiovascular ageing
Feng, Z., Yuan, X., Yi, W., Gao, F., Sun, Y., & Zhang, X. (2025) · Ageing Research Reviews · doi:10.1016/j.arr.2025.102848 · Cited by 7
What Is the Potential Relevance of Growth and Differentiation Factor-15 in Neurologic Disease?
Benarroch, E. E. (2025) · Neurology · doi:10.1212/wnl.0000000000214131 · Cited by 6
Schmid, A., Wilfurth, E., Höpfinger, A., Behrendt, M., Islami, E., Karrasch, T., Berghoff, M., & Schäffler, A. (2025) · Scientific Reports · doi:10.1038/s41598-025-14846-8 · Cited by 5
Adipose Tissue Lipid Metabolism During Exercise
Horowitz, J. F. (2022) · Physiology in health and disease · doi:10.1007/978-3-030-94305-9_7 · Cited by 5
The role of tissue oxygenation in obesity-related cardiometabolic complications
Li, G., Meex, R. C. R., & Goossens, G. H. (2024) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-024-09910-z · Cited by 5
Giannakogeorgou, A., KAHL, S., Granata, C., Heilmann, G., Mastrototaro, L., Dewidar, B., Bobrov, P., Esposito, I., Yavas, A., Trenkamp, S., et al. (2025) · Metabolism · doi:10.1016/j.metabol.2025.156391 · Cited by 4
Translating In Vitro Models of Exercise in Human Muscle Cells: A Mitocentric View
Yeo, R. X., Noone, J., & Sparks, L. M. (2023) · Exercise and Sport Sciences Reviews · doi:10.1249/jes.0000000000000330 · Cited by 4
Lunde, N. N., Osoble, N. M. M., Dalmao‐Fernández, A., Antobreh, A. S., Jafari, A., Singh, S. K., Nyman, T. A., Rustan, A. C., Solberg, R., & Thoresen, G. H. (2023) · Biomedicines · doi:10.3390/biomedicines11112908 · Cited by 3
“This approach has previously been used to explore changes in, e.g., lipolysis and gene expression induced by conditioned medium given to the acceptor cells [30,31].”
MethodMarques, S. S., Liebaug, A., Maurer, S., Rothenbacher, D., Brenner, R. E., & Riegger, J. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.04.10.588843 · Cited by 3
James, E., Frampton, J., Murphy, K. G., & Chambers, E. S. (2025) · Journal of the Endocrine Society · doi:10.1210/jendso/bvaf013 · Cited by 2
“A limitation of previous studies examining the impact of acute exercise on GDF-15 release is the absence of a time-matched, resting control arm [3, 4, 7, 8]; thus exercise-induced changes cannot be distinguished from possible diurnal secretory responses [25].”
Sun, Y., Tang, S., Jingwei, L., Bing, W., Xu, J., Busu, L., Zhao, B. T., Ji, K., & Yan, C. (2025) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-025-03651-1 · Cited by 2
“Additionally, GDF15 binds to the glial cell line-derived neurotrophic factor receptor alpha-like (GFRAL) receptor, which interacts with its tyrosine kinase coreceptor rear-ranged during transfection (RET) to initiate a signaling cascade that may activate various intracellular pathways [7].”
Exercise Suppresses Appetite in Obesity: A Biochemical, Metabolic, and Molecular Approach
Razi, O., Zamani, N., de Moraes, C., Laher, I., & Hadjicharalambous, M. (2025) · Applied Sciences · doi:10.3390/app15116191 · Cited by 4
Metadata
- Authors
- Laurens, C., Parmar, A., Murphy, E., Carper, D., Lair, B., Maes, P., Vion, J., Boulet, N., Fontaine, C., Marquès, M., Larrouy, D., Harant, I., Thalamas, C., Montastier, E., Caspar-Bauguil, S., Bourlier, V., Tavernier, G., Grolleau, J.-L., Bouloumié, A., Langin, D., Viguerie, N., Bertile, F., Blanc, S., de Glisezinski, I., O’Gorman, D., & Moro, C.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Université Toulouse III - Paul Sabatier (FR)
- Dublin City University (IE)
- Inserm, UMR1048, Institute of Metabolic and Cardiovascular Diseases, Toulouse, France.
- Inserm (FR)
- Centre d’Investigation Clinique 1436 (FR)
- ORCID
- Laurens, Claire
- Murphy, Enda
- Carper, Deborah
- Lair, Benjamin
- Vion, Julie
- Boulet, Nathalie
- Fontaine, Coralie
- Larrouy, Dominique
- Harant, Isabelle
- Thalamas, Claire
- Montastier, Emilie
- Caspar-Bauguil, Sylvie
- Bourlier, Virginie
- Tavernier, Geneviève
- Bouloumié, Anne
- Langin, Dominique
- Viguerie, Nathalie
- Bertile, Fabrice
- de Glisezinski, Isabelle
- O’Gorman, Donal
- Moro, Cedric
- Venue
- JCI Insight
- Published
- 2020-03-26
- Volume
- 5
- Issue
- 6
- Pages
- e131870
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC7213799
- OpenAlex
- W3008261843
- Cited by
- 135
- References
- 54
- Citations by year
- 2026: 16 · 2025: 24 · 2024: 25 · 2023: 13 · 2022: 20 · 2021: 27 · 2020: 10
- FWCI
- 13.17
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- JCI Insight (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Funders
- Agence Nationale de la Recherche (ANR-10-INBS-0008, ANR-10-INSB-08, ANR-10-INSB-08–03, ANR-10)
- Institut National de la Santé et de la Recherche Médicale
- Centre National d’Etudes Spatiales
- Centre National de la Recherche Scientifique
- Institut Universitaire de France
- Société Française de Nutrition
- Région Occitanie Pyrénées-Méditerranée
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › GDF15 and Related Biomarkers
- Health Sciences › Medicine › Physiology (medical) › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Physiology (medical) › Exercise and Physiological Responses
- Keywords
- growth and differentiation factor 15, GDF15, myokines, exerkines, skeletal muscle contraction, physical activity, lipolysis, adipose tissue, myotubes, electrical pulse stimulation
- MeSH terms
- Adult, Humans, Lipolysis, Male, Exercise, Muscle, Skeletal, Growth Differentiation Factor 15
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