IL-6 deletion decreased REV-ERBα protein and influenced autophagy and mitochondrial markers in the skeletal muscle after acute exercise
Open accessAbstract
Interleukin 6 (IL-6) acts as a pro and anti-inflammatory cytokine, has an intense correlation with exercise intensity, and activates various pathways such as autophagy and mitochondrial unfolded protein response. Also, IL-6 is interconnected to circadian clock-related inflammation and can be suppressed by the nuclear receptor subfamily 1, group D, member 1 (Nr1d1, protein product REV-ERBα). Since IL-6 is linked to physical exercise-modulated metabolic pathways such as autophagy and mitochondrial metabolism, we investigated the relationship of IL-6 with REV-ERBα in the adaptations of these molecular pathways in response to acute intense physical exercise in skeletal muscle. The present study was divided into three experiments. In the first one, wild-type (WT) and IL-6 knockout (IL-6 KO) mice were divided into three groups: Basal time (Basal; sacrificed before the acute exercise), 1 hour (1hr post-Ex; sacrificed 1 hour after the acute exercise), and 3 hours (3hr post-Ex; sacrificed 3 hours after the acute exercise). In the second experiment, C2C12 cells received IL-6 physiological concentrations or REV-ERBα agonist, SR9009. In the last experiment, WT mice received SR9009 injections. After the protocols, the gastrocnemius muscle or the cells were collected for reverse transcription-quantitative polymerase chain reaction (RTq-PCR) and immunoblotting techniques. In summary, the downregulation of REV-ERBα, autophagic flux, and most mitochondrial genes was verified in the IL-6 KO mice independent of exercise. The WT and IL-6 KO treated with SR9009 showed an upregulation of autophagic genes. C2C12 cells receiving IL-6 did not modulate the Nr1d1 mRNA levels but upregulated the expression of some mitochondrial genes. However, when treated with SR9009, IL-6 and mitochondrial gene expression were upregulated in C2C12 cells. The autophagic flux in C2C12 suggest the participation of REV-ERBα protein in the IL-6-induced autophagy. In conclusion, the present study verified that the adaptations required through physical exercise (increases in mitochondrial content and improvement of autophagy machinery) might be intermediated by an interaction between IL-6 and REVERBα.
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Acute exhaustive treadmill exercise triggered increased mitochondrial respiration and mitochondrial biogenesis in mice, suggesting beneficial adaptations of physical exercise may be driven by interaction between IL-6 and REVERBα.
“An acute exhaustive treadmill exercise (20 m/min for 90 min) triggered increased mitochondrial respiration and mitochondrial biogenesis in mice, suggesting that the beneficial adaptations of physical exercise, such as enhanced mitochondrial content and improved autophagy, may be driven by the interaction between IL-6 and REVERBα [91] (Table 1).”
From Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis (2025) · cites this paper as [91]
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- Authors
- Pinto, A. P., Muñoz, V. R., da Rocha, A. L., Rovina, R. L., Ferrari, G. D., Alberici, L. C., Simabuco, F. M., Teixeira, G. R., Pauli, J. R., de Moura, L. P., Cintra, D. E., Ropelle, E. R., Freitas, E. C., Rivas, D. A., & da Silva, A. S. R.
- Affiliations
- Universidade de São Paulo (BR)
- Universidade Estadual de Campinas (UNICAMP) (BR)
- Universidade Estadual Paulista (Unesp) (BR)
- ORCID
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2022-10-13
- Volume
- 13
- Pages
- 953272-953272
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC9608639
- OpenAlex
- W4304892066
- Cited by
- 14
- References
- 47
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 3 · 2023: 3
- FWCI
- 1.19
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Fundação de Amparo à Pesquisa do Estado de São Paulo (2017/12765-2, 2018/14818-9, 2019/11820-5, 2019/21709-4, 2020/13443-1, 2021/08692-5, 2021/08693-1)
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
- Topics
- Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Complementary and alternative medicine › Cardiovascular and exercise physiology
- Keywords
- interleukin-6, NR1D1, autophagy, mitochondrial biogenesis, skeletal muscle, acute exercise, SR9009, circadian clock, mitochondrial unfolded protein response, IL-6 knockout mice, C2C12 myoblasts, gastrocnemius
- MeSH terms
- Animals, Autophagy, Pyrrolidines, Thiophenes, Biomarkers, Gene Products, rev, Interleukin-6, Muscle, Skeletal, Mice, Nuclear Receptor Subfamily 1, Group D, Member 1
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