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.