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

Abstract

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 CDMRL 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.

Successful metabolic adaptations leading to the prevention of high fat diet-induced murine cardiac remodeling

“…HFD and obesity in mice lead to cardiac remodeling, which is detected as increased heart mass, increased septal cross-section, increased cardiac fibrosis, and decreased cardiac function [ 8 ]. Because MRL mice are globally resistant to HFD pathologies [ 9 ], we wanted to determine whether MRL mice develop cardiomyopathy from HFD-induced obesity and possible compensatory protective mechanisms if they did not.…”

“…The obese HFD MRL mice remain pathology free despite having gained as much weight as the HFD B6 mice [ 9 ]. The HFD MRL mice do not become hyperglycemic, and respond normally to insulin and glucose tolerance tests.…”

“…The control diet (CD) MRL skeletal muscles contain increased basal AMPK and pAMPK [ 13 ]. The HFD MRL skeletal muscles respond and adapt to the HFD by increasing their AMPK and pAMPK levels even more than the basal levels [ 9 ]. pAMPK is central to skeletal muscle metabolism at a number of important decision points [ 14 ].…”

High fat diet accelerates cartilage repair in DBA/1 mice

“…However, these studies used young adult C57BL/6 mice and this strain of mice, in contrast to DBA/1 mice, does not possess cartilage repair capabilities Next to DBA/1 mice, MRL/MpJ mice are known to possess cartilage repair capabilities . Interestingly, these mice gained weight and fat mass, but did not develop the major metabolic changes seen in C57BL/6 mice after being fed a HFD . Our mice gained weight, even only after 2 weeks of HFD and continued to increase weight during the 24 weeks of the study, but did not develop major metabolic changes.…”

Enhanced cartilage repair in ‘healer’ mice—New leads in the search for better clinical options for cartilage repair

“…Collectively, these studies suggest that MRL/MpJ mice have an intrinsic ability to bypass the normal fibrotic ‘repair’ response and instead implement a more ‘regenerative’ program of tissue restoration. Enhanced healing has been extended beyond directed tissue damage with the recent finding that MRL/MpJ mice are also resistant to high fat diet-induced metabolic changes, including type-2 diabetes [45] and cardiac remodeling [46]. However, it is important to note that not all injuries heal better in the MRL/MpJ strain.…”