Date of Award
van Wyk, Paula
Regeneration, S1P, Skeletal Muscle, Sphingosine-1-Phosphate, Type 1 Diabetes
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Skeletal muscle is an adaptive tissue that possesses an innate ability to fully regenerate from a damaging stimulus. Type 1 diabetes mellitus (T1DM) elicits a pathophysiological environment that prevents normal skeletal muscle regeneration by dysregulating key events in the regenerative process. It has been shown that the sphingosine-1-phosphate (S1P) response to skeletal muscle damage is blunted in murine models of T1DM. S1P content normally increases in skeletal muscle acutely (within seven days) following damage to promote regeneration, and an absence of this response results in inadequate recovery. Thus, the lack of S1P accumulation seen in skeletal muscle of diabetic rodents following damage has the potential to contribute to impaired muscle regeneration. This investigation aimed to elucidate the mechanisms underlying this response by assessing: 1) S1P content via Liquid-Chromatography Mass-Spectrometry and 2) expression level of proteins that regulate S1P content via SDS-PAGE and Western Blot analysis. Results from this study show a blunted S1P response to skeletal muscle damage in a T1DM model as S1P content is reduced in Akita mice five days into regeneration. Furthermore, it was found that while sphingosine lyase (SPL) expression increased in both the T1DM models and WT mice following muscle damage, this expression was significantly greater in the diabetic condition. Total sphingosine kinase 1 content was also found to be increased five days following damage, but there was no significant effect of diabetes. Thus, the greater expression of SPL in the T1DM model suggests that S1P is degraded at a faster rate, preventing the normal accumulation of S1P following skeletal muscle damage. Future research should aim to identify the cause of this overexpression and the impact it has on skeletal muscle regeneration.
Mallender, Michael, "Exploring an Impaired Sphingosine-1-Phosphate Response to Skeletal Muscle Damage in a Murine Model of Type 1 Diabetes Mellitus" (2018). Electronic Theses and Dissertations. 7540.