Injectable skeletal muscle constructs overexpressing GLUT4 for type 2 diabetes intervention

Skeletal muscle tissue engineering aims to repair tissue defects caused by injury, cancer, metabolic or neuromuscular disease. The need for invasive implantation techniques often limits the implantation of large tissue constructs or repeated treatments. Recent studies have reported on the development of injectable scaffolds for tissue engineering; however, fabrication of skeletal muscle tissue is particularly challenging due to the large size of human myotubes and the required mechanical properties. This work developed a collagen-based shape-memory scaffold supportive of skeletal muscle tissue growth and differentiation in vitro and maintained shape post-injection in vivo. The injectable engineered muscle construct was intramuscularly delivered via a syringe needle and integrated successfully with the native muscle tissue. We demonstrated the system's potential on a Type 2 diabetes mouse model. A prominent early sign of type 2 diabetes is the reduction in GLUT4 expression and translocation in skeletal muscle; therefore, based on a previous work published by our group, we created injectable GLUT4-overexpressing muscle constructs. Following injection, GLUT4 overexpressing skeletal muscle tissue retained its shape-memory properties and viability and improved glucose homeostasis in the diabetic mice. This work demonstrated successful minimally invasive delivery of engineered muscle tissue and potential treatment for chronic muscle-related conditions. Statement of significance: Type 2 diabetes is a widespread metabolic disorder characterized by insulin resistance and impaired glucose regulation. This study offers a minimally invasive approach to treatment through the development of an injectable skeletal muscle construct overexpressing GLUT4 to improve glucose homeostasis. Unlike traditional surgical methods, this minimally invasive system employs a collagen-based scaffold with shape-memory properties, enabling effective tissue delivery and integration. Existing therapies are limited in addressing chronic metabolic disorders that require repeated interventions. Our work fills that gap by enhancing muscle function and glucose regulation. The scaffold's unique ability to retain its structure post-injection and support muscle differentiation presents a significant advancement with broad implications for treating metabolic diseases and advancing regenerative medicine.