The Murphy Roths Large (MRL) mouse strain is naturally resistant to high fat diet-induced hyperglycemia

Objective. Due to their previously identified naturally and chronically increased levels of skeletal muscle pAMPK we hypothesized and now investigated whether the MRL/MpJ (MRL) mice would be resistant to high fat diet (HFD)-induced metabolic changes. Materials/methods. Three-week old male MRL and control C57Bl/6 (B6) mice were randomly assigned to 12 weeks of high fat diets (HFD) or control diets (CD). Weekly animal masses and fasting blood glucose measurements were acquired. During the last week of diet intervention, fasted animals were subjected to glucose and insulin tolerance tests. At harvest, tissues were dissected for immunoblots and serum was collected for elisa assays. Results. The MRL mouse strain is known for its ability to regenerate ear punch wounds, cardiac cryoinjury, and skeletal muscle disease. Despite gaining weight and increasing their fat deposits the MRL mice were resistant to all other indicators of HFD-induced metabolic alterations assayed. Only the HFD-B6 mice displayed fasting hyperglycemia, hyperinsulinemia and hypersensitivity to glucose challenge. HFD-MRL mice were indistinguishable from their CD-MRL counterparts in these metrics. Skeletal muscles from the HFD-MRL contained heightened levels of pAMPK, even above their CD counterparts. Conclusions. The MRL mouse strain is the first naturally occurring mouse strain that we are aware of that is resistant to HFD-induced metabolic changes. Furthermore, the increased pAMPK suggests a proximal mechanism for these beneficial metabolic differences. We further hypothesize that these metabolic differences and plasticity provide the basis for the MRL mouse strain's super healing characteristics. This project's ultimate aim is to identify novel therapeutic targets, which specifically increase pAMPK.