Increased AMP-activated protein kinase in skeletal muscles of Murphy Roth Large mice and its potential role in altered metabolism.

Abstract Wild-type Murphy Roth Large (MRL) mice have long been investigated for their superior healing ability when subjected to various wound and disease models. Despite this long history, the mechanisms causing their extraordinary healing ability remain undefined. As we have recently demonstrated that MRL mice with muscular dystrophy are resistant to the associated fibrosis and the Heber-Katz group has demonstrated MRL mitochondrial mutations, we decided to investigate the skeletal muscle metabolic characteristics of the MRL mouse strain compared to the commonly utilized C57BL/6J control mouse strain. We now have evidence demonstrating an altered metabolism in the MRL quadriceps, triceps brachii, and diaphragm of 8-week-old animals compared to tissues from control animals. The MRL skeletal muscles have increased activated phosphorylated AMP-activated protein kinase (pAMPK). The increased pAMPK signaling coincides with increased skeletal muscle mitochondrial content. These metabolic changes may compensate for insufficient oxidative phosphorylation which is demonstrated by altered quantities of proteins involved in oxidative phosphorylation and ex vivo metabolic investigations. We also demonstrate that the MRL muscle cells have increased metabolic physiologic reserve. These data further the investigations into this important and unique mouse strain. Why the MRL mice have increased pAMPK and how increased pAMPK and the resultant metabolic alterations affect the healing ability in the MRL mouse strain is discussed. Understanding the molecular mechanisms surrounding the super healing characteristics of these mice will lead to relevant clinical intervention points. In conclusion, we present novel data of increased mitochondrial content, pAMPK, and glycolytic indicators in MRL skeletal muscles.