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Transglutaminase 2 (TGM2) and Its Novel Targeted Activator in Diabetic Bone Regeneration: From Mechanism to Application

ABSTRACT: To screen and identify key molecule regulating T2DM (Type 2 diabetes mellitus)-impaired bone regeneration, cellular osteogenic potential and mitochondrial function, and to elucidate the regulatory mechanisms of this molecule. Microarray analysis was performed to compare transcriptional profiles between bone marrow mesenchymal stem cells (BMMSCs) derived from normal rats (Wistar) and T2DM rats (GK). BMMSCs were transfected with overexpression plasmids targeting candidate molecule and small interfering RNA (siRNA) was used to silence candidate gene expression, then the osteogenic differentiation potential and mitochondrial function of BMMSCs were assessed. Microarray and qRT-PCR revealed significantly elevated expression of TGM2 in BMMSCs from T2DM rats compared to those from normal rats. TGM2 silencing suppressed osteogenic differentiation and mitochondrial function of BMMSCs, and TGM2 overexpression rescued osteogenic capacity. TGM2 serves as a critical regulator of osteogenic differentiation potential and mitochondrial function in BMMSCs derived from T2DM rats

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE301059 | GEO | 2025/07/02

REPOSITORIES: GEO

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Project description:Skeletal muscle mitochondrial dysfunction is secondary to T2DM and can be improved by long-term regular exercise training Mitochondrial dysfunction has long been implicated to play a causative role in development of type 2 diabetes (T2DM). However, a growing number of recent studies provide data that mitochondrial dysfunction is a consequence of T2DM development. The aim of our study is to clarify in further detail the causal role of mitochondrial dysfunction in T2DM by a comprehensive ex vivo analysis of mitochondrial function combined with global gene expression analysis in muscle of pre-diabetic newly diagnosed untreated T2DM subjects and long-standing insulin treated T2DM subjects compared with age- and BMI-matched controls. In addition, we assessed the impact of long-term interval exercise training on physical activity performance, mitochondrial function and glycemic control in long-standing insulin-treated T2DM subjects. Ex vivo mitochondrial density, quality and functioning was comparable between pre-diabetic subjects and matched controls, however, gene expression analysis showed a switch from carbohydrate toward lipids as energy source in pre-diabetes subjects. In contrast, long-term insulin treated T2DM subjects had slightly decreased mitochondrial density and ex vivo function. Expression of Krebs cycle and OXPHOS related genes were decreased, indicating a decreased capacity to use lipids as an energy source. The insulin-treated T2DM subjects had a lower physical activity level than pre-diabetic and normoglycemic subjects. A 52 weeks exercise training of these subjects increased submaximal oxidative efficiency, increased in vivo PCr recovery rate, as well as mildly increased in vitro mitochondrial function. Gene expression of β-oxidation, Krebs cycle and OXPHOS-related genes was increased. Our data demonstrate that mitochondrial dysfunction is rather a consequence than a causative factor in T2DM development as it was only detected in overt diabetes and not in early diabetes. Regular exercise training stabilized exogenous insulin requirement and improved mitochondrial functioning, fatty acid oxidation and general physical work load capacity in long-standing insulin-treated T2DM subjects. As such, the present study shows for the first time that long-term exercise interventions are beneficial in this group of complex diabetes patient and may prevent further metabolic deterioration. Insulin-treated T2DM subjects before and after 52 weeks of exercise training (T2DM_0 and T2DM_52), normoglycemic controls (NGT) and pre-diabetes subjects (IGT) and were selected. RNA was extracted from skeletal muscle biopsies and hybridized on Affymetrix microarrays.

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Transglutaminase 2 (TGM2) and Its Novel Targeted Activator in Diabetic Bone Regeneration: From Mechanism to Application

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