SGLT2 inhibitor dapagliflozin mitigates skeletal muscle pathology by modulating key proteins involved in glucose and ion homeostasis in an animal model of heart failure
Elena Conte , Paola Imbrici , Giorgia Dinoi , Brigida Boccanegra , Martina Lanza , Elena Mele , Maria Antonietta Riemma , Konrad Urbanek , Donato Cappetta , Annamaria De Luca , Liberato Berrino , Antonella De Angelis , Antonella Liantonio
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引用次数: 0
Abstract
Heart failure (HF) is a syndrome characterized by dyspnoea, fatigue and exercise intolerance. Among non-cardiac comorbidities which often accompany HF, skeletal muscle abnormalities impact patients’ daily activities and quality of life. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown promise in improving clinical outcomes and enhancing physical performance in HF patients, although their mechanism of action remains unclear. In this context, altered muscle ions and glucose homeostasis may contribute to HF-related muscle changes and serve as indirect targets for SGLT2i effects. To explore this further, we used Dahl salt-sensitive rats fed with a high-salt diet for five weeks and then randomized to receive dapagliflozin (HS + DAP) or vehicle (HS) for the following six weeks. Control animals received a low-salt diet (LS). We investigated whether variations in indexes of glucose and ions homeostasis occur in extensor digitorum longus muscle of this rodent model of HF with preserved ejection fraction and are counteracted by dapagliflozin treatment. Gene and protein expression analysis revealed altered expression of proteins involved in glucose (SGLT2, GLUT4, GPD1) and Ca2+ and Na + homeostasis (NCX3, Ryr1, NHE1/6, Na+/K+-ATPase, Nav1.4) in HS vs LS animals. Furthermore, HS rats showed an increased CaMKII expression in its active phosphorylated form and a change in plasma pH toward acidification. Dapagliflozin treatment counteracted the altered expression of most of the components under investigation, also promoting an amelioration of atrophy indexes and a recovery of plasma pH. Thus, skeletal muscle appears highly responsive to SGLT2i treatment, supporting the potential of these drugs in mitigating HF-related muscle pathology.
期刊介绍:
The European Journal of Pharmacology publishes research papers covering all aspects of experimental pharmacology with focus on the mechanism of action of structurally identified compounds affecting biological systems.
The scope includes:
Behavioural pharmacology
Neuropharmacology and analgesia
Cardiovascular pharmacology
Pulmonary, gastrointestinal and urogenital pharmacology
Endocrine pharmacology
Immunopharmacology and inflammation
Molecular and cellular pharmacology
Regenerative pharmacology
Biologicals and biotherapeutics
Translational pharmacology
Nutriceutical pharmacology.