title: 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/cm(2)) 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.
authors.affiliation: Program in Physical Therapy and Rehabilitation Sciences, University of Minnesota, 6-155 Jackson Hall, 321 Church St. SE, Minneapolis, MN 55455, USA.
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Call
authors.forename: James M
authors.initials: JM
authors.lastname: Ervasti
authors.forename: Dawn A
authors.initials: DA
authors.lastname: Lowe
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D016189:Dystrophin / Q000172:deficiency* / Q000235:genetics; D004435:Eating; D005247:Feeding Behavior; D005838:Genotype; D008136:Longevity; D051379:Mice; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D009043:Motor Activity; D009119:Muscle Contraction; D053580:Muscle Strength; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D010641:Phenotype; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D049411:Utrophin / Q000172:deficiency* / Q000235:genetics
chemical_list: D016189:Dystrophin; D011993:Recombinant Fusion Proteins; C562337:TAT-mu utrophin fusion protein; D049411:Utrophin