Heart failure (HF) is characterized by severe dyspnea, fatigue, and exercise intolerance. Among comorbidities, skeletal muscle mechanical-metabolic abnormalities are of particular importance as they impair daily activities and quality of life in patients. Sodium-glucose cotransporter2 inhibitors (SGLT2i) increase physical performance in HF, but their mechanisms of action are not completely clear (Wood et al., 2024). Altered muscle ion and glucose homeostasis may play a role in HF-related muscle changes and may be indirect targets of SGLT2i action. We investigated the involvement of proteins mediating Ca2+, Na+, and glucose transport in HF-associated muscle alterations, meanwhile assessing the potential SGLT2i benefit. We used Dahl salt-sensitive rats fed with a high salt diet (HS) for five weeks and then randomized to the SGLT2i dapagliflozin (HS-DAP) for the following six weeks. Outcomes were evaluated on ex vivo indices using EDL muscle. Gene/protein expression analysis showed that HS rats presented increased expression of SGLT2, active CaMKII and related GLUT4 protein, supporting metabolic dysfunction. In addition, we observed changes in proteins mediating Ca2+ and Na+ transport (NCX3, Ryr1, NHE1/6, Na+/K+-ATPase, Nav1.4) suggesting a calcium/sodium overload. Dapagliflozin was able to counteract SGLT2 increase as well as Na+ and Ca2+-related protein alterations. These findings are consistent with ∼20% reduced myofiber atrophy in HS-DAP rats vs HS. These results demonstrate that altered ionic homeostasis and increased SGLT2 expression contribute to HF-related muscle changes. Accordingly, skeletal muscle could be highly responsive to SGLT2i treatment supporting the potential of these drugs in slowing the progression of HF-related skeletal muscle pathology.