We appreciate the commentary on our Review (Chow, L.S. et al. Exerkines in health, resilience and disease. Nat. Rev. Endocrinol. 18, 273–289 (2022))1 by George Brooks and colleagues regarding lactate as a major myokine and exerkine (Brooks, G. A. et al. Lactate as a major myokine and exerkine. Nat. Rev. Endocrinol. https://doi.org/10.1038/s41574-022-00724-0 (2022)2). In our Review1, we mentioned that lactate is a recognized myokine, whose role beyond serving as an energy source to mediate exercise-related effects is increasingly recognized3. Lactate can mediate tissue-to-tissue communication during exercise. The effect of lactate can be autocrine, as exemplified by lactate enhancing the myogenesis of C2C12 cells4. Alternatively, lactate can act in a paracrine or endocrine fashion, as exemplified by stimulation of TGFβ2 release from human adipocytes5, or by activation of CD8+ lymphocytes in a mouse model to delay tumour growth across multiple cancer types6.
We recognize that our Review1 primarily described lactate as an exerkine with direct signalling effects; this description was in the spirit of staying consistent with the direct-signalling descriptions of other exerkines. Notably, a 2022 Nature paper described exercise-stimulated synthesis of N-lactoyl-phenylalanine (Lac-Phe) as an important exerkine that suppressed feeding and reduced obesity7. The commentary by Brooks et al.2 further describes lactate’s metabolic effects in driving exercise-induced adaptions. This expansion is welcome, as Brooks describes lactate serving as a ‘fulcrum of metabolism’ in a 2020 Review8. Lactate has an integral role in the exercise response and a more fleshed-out description of its impact, beyond direct signalling, upholds its valuable contributions.
References
Chow, L. S. et al. Exerkines in health, resilience and disease. Nat. Rev. Endocrinol. 18, 273–289 (2022).
Brooks, G. A. et al. Lactate as a major myokine and exerkine. Nat. Rev. Endocrinol. https://doi.org/10.1038/s41574-022-00724-0 (2022).
Nalbandian, M. & Takeda, M. Lactate as a signaling molecule that regulates exercise-induced adaptations. Biology (Basel) 5, 1–12 (2016).
Willkomm, L. et al. Lactate regulates myogenesis in C2C12 myoblasts in vitro. Stem Cell Res. 12, 742–753 (2014).
Takahashi, H. et al. TGF-β2 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism. Nat. Metab. 1, 291–303 (2019).
Rundqvist, H. et al. Cytotoxic T-cells mediate exercise-induced reductions in tumor growth. eLife 9, e59996 (2020).
Li, V. L. et al. An exercise-inducible metabolite that suppresses feeding and obesity. Nature 606, 785–790 (2022).
Brooks, G. A. Lactate as a fulcrum of metabolism. Redox Biol. 35, 101454 (2020).
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L.S.C. has a Dexcom investigator initiated grant: product only. C.J.L. acts as a consultant for PAIhealth on their Personalized Activity Intelligence applications. A.P. is on an advisory board of Roche Diagnostics. M.P.S. is a Cofounder and scientific advisory board member of Personalis, SensOmics, Qbio, January, Filtricine, Protos, NiMo and Mirvie. He is also an advisor for Genapsys. The other authors declare no competing interests.
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Chow, L.S., Gerszten, R.E., Taylor, J.M. et al. Reply to ‘Lactate as a major myokine and exerkine’. Nat Rev Endocrinol 18, 713 (2022). https://doi.org/10.1038/s41574-022-00726-y
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DOI: https://doi.org/10.1038/s41574-022-00726-y