Palmitoylethanolamide (PEA) regulates cell cycle progression and promotes an anti-inflammatory transcriptomic signature in C2C12 skeletal muscle cells

Cole, PL, Gillham, SH ORCID: 0000-0002-1745-0118, Viggars, MR ORCID: 0000-0002-0722-7051, Close, GL ORCID: 0000-0002-7210-9553 and Owens, DJ ORCID: 0000-0002-1908-8677 (2026) Palmitoylethanolamide (PEA) regulates cell cycle progression and promotes an anti-inflammatory transcriptomic signature in C2C12 skeletal muscle cells. Physiological Reports, 14 (4). ISSN 2051-817X

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Abstract

Palmitoylethanolamide (PEA) is an endogenous lipid mediator with immunomodulatory actions, yet its effects in skeletal muscle remain poorly defined. We examined whether PEA influences myogenesis and profiled the acute transcriptomic response of differentiated C2C12 myotubes to 10 μM PEA. PEA decreased myotube number (90.3 ± 10.6 vs. 112.6 ± 10.1 control) while increasing nuclear fusion index (37.8 ± 5.7% vs. 30.7 ± 3.2%); myotube area was unchanged. In myoblasts, 24 h PEA increased G0/G1 (48.2 ± 1.2% vs. 42.3 ± 1.9%) and reduced S-phase (21.7 ± 1.2% vs. 25.5 ± 1.2%), consistent with G1 arrest. RNA sequencing identified 1952 differentially expressed genes enriched for cytokine–receptor interactions and inflammatory signaling. PEA downregulated NF-κB target cytokines while upregulating interferon-related and chemokine genes, indicating an anti-inflammatory/immune-priming profile. N-acylethanolamine acid amidase was highly expressed and induced, whereas fatty acid amide hydrolase remained low and unchanged, suggesting muscle-specific reliance on NAAA metabolism. These data show that PEA biases skeletal muscle toward a less proliferative but more fused and inflammation-resolving phenotype, with transcriptional reprogramming of immune pathways and preferential NAAA engagement. These findings motivate in vivo studies to test whether such actions benefit muscle regeneration, adaptation, or anti-atrophy interventions.

Item Type:	Article
Uncontrolled Keywords:	immunomodulation; myogenesis; N-acylethanolamines; Muscle, Skeletal; Cell Line; Animals; Mice; Ethanolamines; Amides; Palmitic Acids; Cell Cycle; Muscle Development; Muscle Fibers, Skeletal; Transcriptome; N‐acylethanolamines; immunomodulation; myogenesis; Palmitic Acids; Animals; Ethanolamines; Mice; Transcriptome; Amides; Cell Cycle; Cell Line; Muscle, Skeletal; Muscle Fibers, Skeletal; Muscle Development; 3208 Medical Physiology; 32 Biomedical and Clinical Sciences; Genetics; 2.1 Biological and endogenous factors; 1.1 Normal biological development and functioning; Inflammatory and immune system; Musculoskeletal; Palmitic Acids; Animals; Ethanolamines; Mice; Transcriptome; Amides; Cell Cycle; Cell Line; Muscle, Skeletal; Muscle Fibers, Skeletal; Muscle Development; 0606 Physiology; 1103 Clinical Sciences; 1116 Medical Physiology; 3208 Medical physiology
Subjects:	Q Science > QP Physiology
Divisions:	Sport and Exercise Sciences
Publisher:	Wiley
Date of acceptance:	3 February 2026
Date of first compliant Open Access:	4 March 2026
Date Deposited:	04 Mar 2026 15:45
Last Modified:	04 Mar 2026 15:45
DOI or ID number:	10.14814/phy2.70780
URI:	https://researchonline.ljmu.ac.uk/id/eprint/28195

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