Streptococcus salivarius subsp. thermophilus ST-G30 Prevents Dexamethasone-Induced Muscle Atrophy in C2C12 Myotubes

<b>Background/Objectives:</b> Sarcopenia is characterized by loss of muscle mass and strength and is associated with aging. Recently, its links with the gut-muscle axis have been reported, suggesting that probiotics could influence muscle health. <b>Methods:</b> In the present study, we investigated the protective roles of two lactic acid bacteria strains, <i>Streptococcus salivarius</i> subsp. <i>thermophilus</i> ST-G30 (ST-G30) and <i>Lacticaseibacillus paracasei</i> LPc-G110 (LPc-G110), on skeletal muscle atrophy induced by dexamethasone (DEX) in C2C12 myotubes. <b>Results:</b> Our results demonstrated that ST-G30 significantly alleviated DEX-induced myotube atrophy by increasing the myotubes' diameter (25.95 ± 1.28 vs. 15.30 ± 0.30 μm, <i>p</i> < 0.01), improving the fusion index (48.35 ± 1.75 vs. 22.16 ± 2.36%, <i>p</i> < 0.0001), and increasing the protein content (1.78 ± 0.02 vs. 1.56 ± 0.01 mg/mL, <i>p</i> < 0.05) and myotube length (0.61 ± 0.05 vs. 0.33 ± 0.01, <i>p</i> < 0.05), whereas LPc-G110 showed no significant effect on these phenotypes (<i>p</i> > 0.05). Transcriptomic analysis reveals that ST-G30 modulates critical signaling pathways and biological processes related to skeletal muscle health. In the current study, KEGG enrichment analysis and WGCNA enabled identification of the PI3K-Akt signaling pathway as a key regulator of these processes, highlighting its essential role in mitigating DEX-induced muscle atrophy. Furthermore, the overlapping DEGs associated with the PI3K-Akt signaling pathway showed strong correlations with muscle atrophy-related indices. <b>Conclusions:</b> These findings underscore the potential of ST-G30 as a promising anti-muscle atrophy supplement and provide valuable insights for developing strategies to prevent and treat glucocorticoid-induced skeletal muscle atrophy.