Loss of mitochondrial protease YME1L in the muscle leads to fiber type switch and metabolic dysfunction Sofia Ahola1, Sebastian Kallabis1, Tim Wai2, Thomas Langer1,3*, 1CECAD Research Center, University of Cologne; 2Faculté de Médecine, Université de Paris; 3Max Planck Institute for Biology of Ageing, Cologne *Corresponding Author
Type 2 diabetes (T2D) is a metabolic disease characterized by high blood glucose due to insulin resistance combined with systemic increase in lipids. The main cause for the disease is thought to be obesity, yet the underlying pathophysiology is poorly known. Skeletal muscle, liver and adipose tissue are the main contributors to the development of peripheral insulin resistance making these tissues interesting targets for research and treatment. Insulin resistant skeletal muscle accumulates intracellular lipids, show reduced expression of fatty acid oxidation and impairment of mitochondrial function. Disruption in mitochondrial function in skeletal muscle is common finding in T2D and also precedes the disease. In this study we are aiming to better understand what are the underlying changes in muscle mitochondrial metabolism that can lead to metabolic syndrome and T2D. We are utilizing a mouse model that lacks mitochondrial protease YME1L in the muscle tissue (YKO). YME1L is governing the mitochondrial proteome and fusion process and loss of YME1L leads in to mitochondrial fragmentation. We have previously published that these mice are glucose intolerant due to systemic down regulation of insulin production, and insulin hypersensitive. Here we characterize YKO mice in more detailed focusing on the skeletal muscle. YKO mice are exercise intolerant and the muscle shows accumulation of internalized nuclei and fiber size variation. However, there is no inflammation or increase in atrophy markers. By using single muscle fiber proteomic analysis we show that loss of YME1L leads to fiber type switch from more oxidative to glycolytic fiber type and that the glycolytic fiber proteome shows increased fatty acid oxidation and decreased glucose utilization. Our preliminary data indicates that phenotype is progressive and might be due to incomplete differentiation of these muscle fibers. We suggest that YME1L is needed for proper metabolic determination of the cell and when this process is compromised, muscle is unable properly control the whole body glucose metabolism here.
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