CXCL14 Promotes Skeletal Muscle Mass Growth and Attenuates Lipopolysaccharide‐ and Dexamethasone‐Induced Muscle Atrophy in Cultured Myotubes and Mouse Models

BackgroundSkeletal muscle mass is regulated by secretory factors derived from myofibers and muscle‐resident cells. Identifying these factors and understanding their mechanisms is critical for combating muscle wasting disorders. This experimental study investigates the role of CXCL14, a chemokine primarily secreted by fibro‐adipogenic progenitors (FAPs) residing in muscle, in regulating muscle mass.MethodsThis study was conducted at the Soonchunhyang Institute of Medi‐bio Science (SIMS), South Korea, between August 2020 and June 2025. Mouse C2C12 myotubes and primary human myotubes were treated with recombinant CXCL14, with or without co‐treatment using Rps6kb1 siRNA, lipopolysaccharide (LPS) or dexamethasone (DEX). Myotube mass index (MMI) was measured. Expression of AKT‐S6 kinase (S6K), FOXO‐Atrogin‐1/MuRF‐1 signalling components and myosin heavy chains (MyHCs) was assessed via Western blotting. Eight‐week‐old male mice were used: ICR mice for electroporation experiments and C57BL/6N strain for LPS and DEX atrophy models. Cxcl14 expression plasmids were electroporated into tibialis anterior (TA) muscles, with or without LPS or DEX treatment. Cross‐sectional area (CSA) of myofibers was measured; Western blotting and RNA sequencing were used to analyse molecular responses. Statistical analyses included one‐way ANOVA with Tukey's post hoc test, repeated‐measures ANOVA with Dunnett's post hoc test, Kruskal–Wallis test with Dunn's post hoc test and unpaired Student's t‐test, as appropriate.ResultsCXCL14 induced hypertrophy in C2C12‐derived myotubes: (MMI [μm2]: 100 ng/mL CXCL14, 1345 ± 50.97 [95% CI: 1237–1453], vs. control, 897.9 ± 33.33 [95% CI: 829.8–996], p ≤ 0.0001). Cxcl14 overexpression in mouse TA muscles significantly increased muscle mass: (CSA [μm2]: HA‐CXCL14: 1408 ± 15.42 [95% CI: 1378–1438]; CXCL14‐Myc: 1499 ± 17.18 [95% CI: 1464–1534]; control: 870.1 ± 11.25 [95% CI: 848.1–892.2], p ≤ 0.0001). CXCL14 activated the AKT‐S6K pathway and inhibited the FOXO‐Atrogin‐1/MuRF‐1 pathway in both in vitro and in vivo models. CXCL14 effectively reversed LPS‐ and DEX‐induced atrophy in both C2C12 myotubes and TA muscles, as demonstrated by corresponding increases MMI and CSA (all p ≤ 0.0001). CXCL14 also promoted hypertrophy in primary human myotubes in vitro (MMI [μm2]: 100 ng/mL CXCL14, 3481 ± 242.6 [95% CI: 2973–3989] vs. control, 2549 ± 114.7 [95% CI: 2310–2787], p ≤ 0.001) and significantly reversed atrophy induced by LPS and DEX (p ≤ 0.01 to p ≤ 0.0001), accompanying the activation of protein synthesis and inhibition of protein degradation pathways.ConclusionsOur findings identify CXCL14 as a novel regulator of skeletal muscle mass and highlight its therapeutic potential in preventing or reversing muscle atrophy associated with ageing and diseases in humans.