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

Call JA, Ervasti JM, Lowe DA. Tat-mu Utrophin mitigates the pathophysiology of dystrophin and utrophin double-knockout mice. J Appl Physiol 111: 200-205, 2011. First published May 12, 2011; doi:10.1152/japplphysiol.00248.2011.-Previously, we demonstrated functional substitution of dystrophin by TAT-mu Utrophin (TAT-mu Utr) in dystrophin-deficient mdx mice. Herein, we addressed whether TAT-mu Utr 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-mu Utr protein administration against placebo-treated mdx:utr(-/-) mice (PBS). Additionally, skeletal muscles from TAT-mu Utr and PBS mice were tested in vivo and ex vivo for strength and susceptibility to eccentric contraction-induced injury. We found the TAT-mu Utr 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-mu Utr mice (e.g., 364 vs. 201 m ambulation/24 h). The extensor digitorum longus muscles of TAT-mu Utr-treated double-knockout mice also displayed increased force-generating capacity ex vivo (8.3 vs. 6.4 N/cm(2)) and decreased susceptibility to injury ex vivo and in vivo. These data indicate that the functional benefits of TAT-mu Utr 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.