Use of HSAfemale mice as a model for the study of myotonic dystrophy type I.

Abstract

HSAmice are the most broadly used animal model for studying myotonic dystrophy type I (DM1). However, so far, HSApreclinical studies have often excluded female mice or failed to document the biological sex of the animals. This leaves an unwanted knowledge gap concerning the differential development of DM1 in males and females, particularly considering that the disease has a different clinical presentation in men and women. Here we compared typical functional measurements, histological features, molecular phenotypes and biochemical plasma profiles in the muscles of male and female HSAmice in search of any significant between-sex differences that could justify this exclusion of female mice in HSAstudies and, critically, in candidate therapy assays performed with this model. We found no fundamental differences between HSAmales and females during disease development. Both sexes presented comparable functional and tissue phenotypes, with similar molecular muscle profiles. The only sex differences and significant interactions observed were in plasma biochemical parameters, which are also intrinsically variable in patients with DM1. In addition, we tested the influence of age on these measurements. We therefore suggest including female HSAmice in regular DM1 studies, and recommend documenting the sex of animals, especially in studies focusing on metabolic alterations. This will allow researchers to detect and report any potential differences between male and female HSAmice, especially regarding the efficacy of experimental treatments that could be relevant to patients with DM1.