<p>S-ketamine is recognized as a rapid-acting antidepressant, exerting its effects primarily through activation of the mTOR signaling pathway in the brain, which plays a key role in neuroplasticity. Given the shared molecular mechanisms between brain and skeletal muscle, we investigated whether S-ketamine can also modulate regulatory proteins involved in muscle protein synthesis (MPS) and muscle protein breakdown (MPB) in skeletal muscle. Adult female Flinders Sensitive Line rats received a single intraperitoneal injection of S-ketamine (20&#xa0;mg/kg) or saline, and soleus and extensor digitorum longus (EDL) muscles were collected two hours post-injection for protein analysis using Western blot. S-ketamine significantly increased phosphorylated mTOR (p-mTOR^Ser2448) in both soleus and EDL, while total ULK1 protein expression was elevated in soleus. These findings suggest that S-ketamine can stimulate mTOR-related signaling in skeletal muscle, potentially enhancing MPS, although the activation was limited to specific signaling proteins. The results provide novel insights into the peripheral effects of S-ketamine beyond the central nervous system, highlighting the potential relevance for skeletal muscle physiology and anabolic regulation. Future studies are warranted to determine the temporal dynamics of these effects, the dose-dependence, and the impact of repeated administration on muscle hypertrophy. Overall, this study expands understanding of S-ketamine’s systemic actions and raises new questions regarding its potential as a modulator of skeletal muscle protein metabolism.</p>