The Combination of Endurance Exercise and SGTC (Salvia-Ginseng-Trigonella-Cinnamon) Ameliorate Mitochondrial Markers' Overexpression with Sufficient ATP Production in the Skeletal Muscle of Mice Fed AGEs-rich High-fat Diet

Background: Skeletal muscle mitochondria is one of the most important affected sites of T2DM and its molecular mechanism is yet to be elucidated. Some recent theories believed that mitochondrial markers are upregulated in response to high fat induced T2DM; however, the reasons and the affected factors are still uncertain. In this regard, we aimed to investigate the effect of high fat induced T2DM on mitochondrial markers of skeletal muscle, and an herbal component along with endurance exercise, as probable treatments, in AGE-rich high-fat diet (AGEs-HFD) induced T2DM mice.

Methods: T2DM was induced by 16 weeks of AGEs-HFD consumption in male C57BL/6 mice, followed by 8 weeks of drugs ingestion and endurance exercise treatments (n = 6 in each group and total number of 42 mice). The herbal component was an aquatic extract of Salvia officinalis, Trigonella foenum-graecum, Panax ginseng, and Cinnamomum zeylanicum, termed "SGTC". We then examined the relative expression of several mitochondrial markers, including Ppargc1α, Tfam, and electron transport chain genes and ATP levels, in skeletal muscle samples.

Results: T2DM was successfully induced according to morphological, biochemical, and molecular observations. All mitochondrial markers, including Ppargc1a, Tfam, Cpt2, and electron transport chain genes, were upregulated in T2DM group compared to controls with no significant changes in the ATP levels. Most mitochondrial markers were downregulated by drug treatment compared to T2DM, but the ATP level was not significantly altered. All mitochondrial markers were upregulated in exercised group compared to T2DM with mild increase in the ATP level. The Ex + SGTC group had moderate level of mitochondrial markers compared to T2DM, but the highest ATP production.

Conclusion: The highly significant overexpression of mitochondrial markers may be in response to free fatty acid overload. However, the lack of significant change in the ATP level may be a result of ROS generation due to electron leakage in the AGEsRAGE axis and electron transport chain. Almost all treatments ameliorate mitochondrial markers' overexpression. The SGTC appears to regulate this with its antioxidant properties. Instead, exercise upregulated mitochondrial markers efficiently; however, the most efficient results, i.e. the most ATP production among the treatments, were observed in the Ex + SGTC group.