The Muscle Ankyrin Repeat Proteins Are Hypoxia-Sensitive: In Vivo mRNA Expression in the Hypoxia-Tolerant Blind Subterranean Mole Rat, Spalax ehrenbergi

The muscle ankyrin repeat proteins (MARPs), also known as muscle stretch proteins, are members of a conserved family of genes known to be induced under stress conditions. The three primary members, cardiac ankyrin repeat protein (CARP), Ankyrin Repeat Domain 2 (ARPP), and diabetes-related ankyrin repeat protein (DARP) are expressed in cardiac and skeletal muscle, binding to the giant protein titin. In addition, both CARP and ARPP are proposed to have regulatory functions, shuttling to the nucleus and serving as a liaison between mechanical stress and the transcriptional response. In mouse and human models, CARP is induced during wound healing, denervation, neurogenesis, and angiogenesis; ARPP during an immobilized stretch; DARP is up-regulated in type 2 diabetes, as well as brown adipose tissue, suggesting a role in energy metabolism. Most animal models have focused on stretch response stress; however, little is known about the response of MARPs to hypoxic stress. The blind subterranean mole rat is a model for hypoxia tolerance with the ability to survive extremely hypoxic and hypercapnic underground conditions. Following observations that CARP is differentially expressed in the Spalax muscle in response to hypoxia, we have sequenced the Spalax orthologs of the MARP proteins and profiled expression patterns under varying levels of hypoxic stress among two Spalax species and Rattus. Results show expression patterns highly correlated to the degree of hypoxic tolerance among the three species. Understanding the differences in MARP expression further elucidates mechanisms of hypoxia tolerance with relevance to human ischemic disease.