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Fructose induces mitochondrial dysfunction and triggers apoptosis in skeletal muscle cells by provoking oxidative stress

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Abstract

Mitochondrial dysfunction in skeletal muscle has been implicated in the development of insulin resistance, a major characteristic of type 2 diabetes. There is evidence that oxidative stress results from the increased production of reactive oxygen species and reactive nitrogen species leads to mitochondrial dysfunction, tissue damage, insulin resistance, and other complications observed in type 2 diabetes. It has been suggested that intake of high fructose contributes to insulin resistance and other metabolic disturbances. However, there is limited information about the direct effect of fructose on the mitochondrial function of skeletal muscle, the major metabolic determinant of whole body insulin activity. Here, we assessed the effect of fructose exposure on mitochondria-mediated mechanisms in skeletal muscle cells. Exposure of L6 myotubes to high fructose stimulated the production of mitochondrial reactive oxygen species and nitric oxide (NO), and the expression of inducible NO synthase. Fructose-induced oxidative stress was associated with increased translocation of nuclear factor erythroid 2-related factor-2 to the nucleus, decreases in mitochondrial DNA content and mitochondrial dysfunctions, as evidenced by decreased activities of citrate synthase and mitochondrial dehydrogenases, loss of mitochondrial membrane potential, decreased activity of the mitochondrial respiratory complexes, and impaired mitochondrial energy metabolism. Furthermore, positive Annexin–propidium iodide staining and altered expression of Bcl-2 family members and caspases in L6 myotubes indicated that the cells progressively became apoptotic upon fructose exposure. Taken together, these findings suggest that exposure of skeletal muscle cells to fructose induced oxidative stress that decreased mitochondrial DNA content and triggered mitochondrial dysfunction, which caused apoptosis.

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Acknowledgments

The authors are thankful for financial support from the Council of Scientific and Industrial Research (CSIR), New Delhi, India in the form of network Project THUNDER (BSC0102) and SMiLE (CSC0111). The authors would also like to thank Dr. Amira Klip for providing L6 cells. NJ, CKM, DRA are supported by Senior Research Fellowship of University Grant Commission (UGC), New Delhi. We are thankful to Mr A.L. Vishwakarma, SAIF Division for flowcytometric analysis. This manuscript bears the CDRI Communication No. 8978.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Biochemistry, CSIR-Central Drug Research Institute, Lucknow, 226031, India

    Natasha Jaiswal, Chandan K. Maurya, Deepti Arha & Akhilesh Kumar Tamrakar

  2. Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500007, India

    Deepa R. Avisetti & Shasi V. Kalivendi

  3. Agroprocessing and Natural Products Division, CSIR-National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram, 695019, India

    Ayyappan Prathapan, Palayyan S. Raj & Kozhiparambil G. Raghu

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  1. Natasha Jaiswal
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Jaiswal, N., Maurya, C.K., Arha, D. et al. Fructose induces mitochondrial dysfunction and triggers apoptosis in skeletal muscle cells by provoking oxidative stress. Apoptosis 20, 930–947 (2015). https://doi.org/10.1007/s10495-015-1128-y

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