Tofogliflozin ameliorates cardiotoxin induced skeletal muscle injury and fibrosis in obesity
Obesity impairs muscle function through effects on lipid metabolism, systemic inflammation, and insulin resistance, leading to muscle loss and reduced regeneration. Tofogliflozin (Tofo), a sodium-glucose cotransporter 2 inhibitor (SGLT2i), exclusively inhibits SGLT2 and is used to treat hyperglycemia in patients with diabetes. The mechanism by which Tofo promotes myogenic potential in an injury model remains elusive. This study investigated Tofo's role in skeletal muscle repair in diet-induced obesity. C57BL/6 J male mice were fed a high-fat diet (HFD) with or without Tofo for 12 weeks. Cardiotoxin (CTX) was used to induce acute injury. We showed that Tofo administration during HFD alleviates obesity-induced disruption in glucose metabolism and upregulates Pax7 and MyoG expression in skeletal muscle, thereby promoting myogenesis following acute injury. Tofo activates fibro-adipogenic progenitors (FAPs) in skeletal muscle, leading to upregulated follistatin (Fst) expression and boosting the recovery process after acute injury. Mechanistically, Tofo prevented the obesity-induced decline in AMPK phosphorylation, rescued the impairment of lipid metabolism, and improved skeletal muscle function, which led to increased exercise tolerance, activation of FAPs, facilitation of skeletal muscle repair, and reduction of fibrosis.
Authors
- Marsel Lino (ORCID: https://orcid.org/0000-0001-9662-6339)
- Yoshiyuki Watanabe (ORCID: https://orcid.org/0000-0001-9037-3596)
- Sana Khalid (ORCID: https://orcid.org/0000-0003-4361-2368)
- Tomonobu Kado (ORCID: https://orcid.org/0000-0002-7750-3023)
- Ayumi Nishimura
- Shiho Fujisaka (ORCID: https://orcid.org/0000-0003-0554-9003)
- Masaru Kato (ORCID: https://orcid.org/0000-0003-1724-5824)
- Muhammad Rahil Aslam (ORCID: https://orcid.org/0000-0003-0684-9147)
- Isao Usui (ORCID: https://orcid.org/0000-0002-4720-4882)
- Kenichi Hirabayashi (ORCID: https://orcid.org/0000-0002-9516-1792)
- Kazuyuki Tobe
- Maki Yokoyama (ORCID: https://orcid.org/0000-0001-7942-6677)
- Yoshiko Igarashi (ORCID: https://orcid.org/0000-0002-1828-3323)
- Allah Nawaz (ORCID: https://orcid.org/0000-0002-1979-9575)
- Yasuhiro Onogi (ORCID: https://orcid.org/0000-0002-7950-8952)
- Jianhui Liu (ORCID: https://orcid.org/0000-0001-8921-7350)
- Muhammad Bilal
- Yagi Kunimasa
- Seiji Yamamoto (ORCID: https://orcid.org/0000-0003-1007-6271)
- Memoona Memoona
- Nguyen Quynh Phuong
- Le Duc Anh
- Waseem Abbas (ORCID: https://orcid.org/0000-0002-3078-4315)
Institutions
- Joslin Diabetes Center (US)
- Harvard University (US)
- Japan Society for the Promotion of Science (JP)
- The Japanese Society of Gastroenterological Surgery (JP)
- Ningbo Medical Center Lihuili Hospital (CN)
- Kanazawa Medical University Hospital (JP)
- University of Toyama (JP)
- Dokkyo Medical University (JP)
Publication Details
- Journal
- Scientific Reports
- Published
- 2025-10-22
- DOI
- https://doi.org/10.1038/s41598-025-12734-9
- Citations
- 2
- Primary Topic
- Muscle Physiology and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Eli Lilly and Company
- Naito Foundation
- Suzuken Memorial Foundation
- Japan Foundation for Applied Enzymology
- Uehara Memorial Foundation
- Japan Association for Diabetes Education and Care
- Novo Nordisk
- Japan Diabetes Society
- Ono Medical Research Foundation
- Yamaguchi Endocrine Research Foundation
- Japan Student Services Organization
- Lotte Foundation
- Japan Diabetes Foundation
- Eli Lilly Japan
- Novo Nordisk Pharma
- Japan Society for the Promotion of Science
- Moonshot Research and Development Program