Skeletal myoblast transplantation for attenuation of hyperglycaemia, hyperinsulinaemia and glucose intolerance in a mouse model of type 2 diabetes mellitus

Abstract

Aims/hypothesis We aimed to demonstrate the feasibility and efficacy of intra-muscular transplantation of human skeletal myoblasts (hSkMs) for attenuation of hyperglycaemia and improvement of insulin sensitivity using a mouse model of type 2 diabetes mellitus. Methods KK Cg-Ay/J mice, aged 12 to 14 weeks, underwent an initial intraperitoneal glucose tolerance test (GTT) and were divided into the following groups: KK control group, basal medium (M199) only; KK myoblast group, with hSkM transplantation; KK fibroblast group, with human fibroblast transplantation. Non-diabetic C57BL mice were used as an additional normal control and also had hSkM transplantation. Cells were transplanted intramuscularly into the skeletal muscles of the mice. All animals were treated with ciclosporin for 6 weeks only. HbA 1c and fasting GTT, as well as serum adiponectin, cholesterol, insulin and triacylglycerol were studied. Results Immunohistochemistry studies showed extensive survival of the transplanted hSkMs in the skeletal muscles at 12 weeks, with nuclei of the hSkMs integrated into the host muscle fibres. Repeat GTT showed a significant decrease in glucose concentrations in the KK myoblast group compared with the KK control and KK fibroblast groups. The KK myoblast group also had reduced mean HbA 1c , cholesterol, insulin and triacylglycerol, and increased adiponectin compared with the KK control and KK fibroblast groups. C57BL mice showed no change in glucose homeostasis after hSkM transplant.

Disease Prevention and Alleviation by Human Myoblast Transplantation

“…As in Ye et al [47], extensive integration of donor myoblast nuclei into host muscle fibers was demonstrated at 12 weeks after HMGT/MTT (Figure 2). Glucose tolerance test showed a significant decrease of blood glucose in the mice of KK myoblast group compared to the KK control and fibroblast groups (Figure 3).…”

“…These upregulation and downregulation in transcriptional pattern levels of the 50 genes after HMGT/MTT represent genetic repair toward attenuating hyperglycaemia and hyperinsulinemia, and improving glucose tolerance in the mouse model (KK) of Type-II diabetes mellitus. Undoubtedly, these studies [47]- [49] provide strong evidence that HMGT/MTT mediates its beneficial effects through myoblast fusion, not only adding new normal myofibers, but replenishing normal copies of the abnormal genes upon nuclear transfer to effect genetic repair of the dystrophic [22] [47]- [49]. Together, they demonstrated the proof-of-concept of HMGT/MTT in developing as a cell therapy and as a gene therapy for hereditary muscle diseases such as muscular dystrophies, hereditary cardiomyopathies, Type-II diabetes and others [25] [27].…”

“…Methods of human myoblast implantation and immunosuppression follow that of Ye et al [47]. Hind limb muscles were harvested and used for study of gene expression profiling.…”

“…If so, one would expect that MTT could replenish the structural and regulatory protein deficits in Type II diabetes via improvement of genetic transcriptional pathways as described later in this article. Indeed, HMGT/MTT alters gene expression profiles of insulin signaling pathway and mitochondrial biogenesis and function in skeletal muscles of diabetic KK Cg-A y /J mice [47] [48] and reduces blood glucose in Type II diabetes patients [49].…”

Thymosin β4 Increases the Potency of Transplanted Mesenchymal Stem Cells for Myocardial Repair

“…Protein expression levels from treated and non-treated sMSCs were determined by western blot analysis as described 21 . Cell lysate was prepared using PhosphoSafe™ Extraction Reagent (Merck, Germany) and protein concentration was determined using Bradford reagent (Bio-Rad Laboratories, USA).…”