Targeting Skeletal Muscle Melatonin-MT₂ Signaling to Attenuate the Obesity-Cancer Axis: A Metabolic Perspective

Mihaela Jurdana^1,*, Lovro Ziberna^2,3
1 Faculty of Health Sciences, University of Primorska, Izola, Slovenia
2 Institute of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
3 Department of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
* Corresponding Author: Mihaela Jurdana. Email: email

BIOCELL https://doi.org/10.32604/biocell.2026.079591

Received 24 January 2026; Accepted 11 March 2026; Published online 25 March 2026

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Abstract

Obesity and metabolic syndrome promote malignancies through chronic inflammation and sustained activation of insulin and insulin-like growth factor-1 (IGF-1) signaling. Skeletal muscle is central to this tumor-promoting milieu because it governs insulin-stimulated glucose disposal, lipid oxidation, and endocrine crosstalk. This narrative review explores whether melatonin signaling in skeletal muscle, particularly via melatonin receptor 2 (MT₂), represents a modifiable node within the obesity–cancer axis. Experimental evidence indicates that melatonin activates MT₂-linked Gi/o and calcium-sensitive pathways converging on phosphoinositide 3-kinase–protein kinase B (PI3K–Akt), extracellular signal-regulated kinases (ERK), and calcium/calmodulin-dependent protein kinase II–adenosine monophosphate-activated protein kinase–peroxisome proliferator-activated receptor gamma coactivator 1-alpha (CaMKII–AMPK–PGC-1α) signaling. These pathways enhance insulin sensitivity, mitochondrial function, and lipid partitioning while reducing myosteatosis and cellular stress. By improving muscle quality, melatonin may lower systemic insulin and IGF-1 drive and inflammatory adipokine tone that fuel tumor-promoting PI3K–Akt–mammalian target of rapamycin (mTOR) signaling. However, human evidence remains limited and timing-dependent. Melatonin exposure in the fed state or near carbohydrate intake may worsen glycemia, particularly in carriers of melatonin receptor 1B (MTNR1B) risk alleles. Chronobiology-informed, genotype-guided trials with detailed muscle phenotyping and cancer-relevant endpoints are warranted.

Keywords

Melatonin; melatonin receptor 1; melatonin receptor 2; melatonin receptor 1A gene; melatonin receptor 1B gene; skeletal muscle; insulin resistance; myosteatosis; sarcopenic obesity; myokines; obesity-related cancer