TAT-μUtrophin mitigates the pathophysiology of dystrophin and utrophin double-knockout mice

Abstract

Previously, we demonstrated functional substitution of dystrophin by TAT-μUtrophin (TAT-μUtr) in dystrophin-deficient mdx mice. Herein, we addressed whether TAT-μUtr could improve the phenotype of dystrophin and utrophin double-knockout ( mdx:utr−/−) mice. Specifically, we quantitatively compared survival and quality of life assessments in mdx:utr−/− mice receiving TAT-μUtr protein administration against placebo-treated mdx:utr−/− mice (PBS). Additionally, skeletal muscles from TAT-μUtr and PBS mice were tested in vivo and ex vivo for strength and susceptibility to eccentric contraction-induced injury. We found the TAT-μUtr treatment extended life span 45% compared with mice administered PBS. This was attributed to significantly increased food consumption (3.1 vs. 1.8 g/24 h) due to improved ability to search for food as daily cage activities were greater in TAT-μUtr mice (e.g., 364 vs. 201 m ambulation/24 h). The extensor digitorum longus muscles of TAT-μUtr-treated double-knockout mice also displayed increased force-generating capacity ex vivo (8.3 vs. 6.4 N/cm2) and decreased susceptibility to injury ex vivo and in vivo. These data indicate that the functional benefits of TAT-μUtr replacement treatment extend to the mdx:utr−/− double-knockout mouse and support its development as a therapy to mitigate muscle weakness in patients with Duchenne muscular dystrophy.