TY - JOUR T1 - Effect of Ibuprofen on Skeletal Muscle of Dysferlin-Null Mice JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 409 LP - 419 DO - 10.1124/jpet.117.244244 VL - 364 IS - 3 AU - Alyssa F. Collier AU - Jessica Gumerson AU - Kimmo Lehtimäki AU - Jukka Puoliväli AU - Jace W. Jones AU - Maureen A. Kane AU - Sankeerth Manne AU - Andrea O’Neill AU - Hillarie P. Windish AU - Toni Ahtoniemi AU - Bradley A. Williams AU - Douglas E. Albrecht AU - Robert J. Bloch Y1 - 2018/03/01 UR - http://jpet.aspetjournals.org/content/364/3/409.abstract N2 - Ibuprofen, a nonsteroidal anti-inflammatory drug, and nitric oxide (NO) donors have been reported to reduce the severity of muscular dystrophies in mice associated with the absence of dystrophin or α-sarcoglycan, but their effects on mice that are dystrophic due to the absence of dysferlin have not been examined. We have tested ibuprofen, as well as isosorbide dinitrate (ISDN), a NO donor, to learn whether used alone or together they protect dysferlin-null muscle in A/J mice from large strain injury (LSI) induced by a series of high strain lengthening contractions. Mice were maintained on chow containing ibuprofen and ISDN for 4 weeks. They were then subjected to LSI and maintained on the drugs for 3 additional days. We measured loss of torque immediately following injury and at day 3 postinjury, fiber necrosis, and macrophage infiltration at day 3 postinjury, and serum levels of the drugs at the time of euthanasia. Loss of torque immediately after injury was not altered by the drugs. However, the torque on day 3 postinjury significantly decreased as a function of ibuprofen concentration in the serum (range, 0.67–8.2 µg/ml), independent of ISDN. The effects of ISDN on torque loss at day 3 postinjury were not significant. In long-term studies of dysferlinopathic BlAJ mice, lower doses of ibuprofen had no effects on muscle morphology, but reduced treadmill running by 40%. Our results indicate that ibuprofen can have deleterious effects on dysferlin-null muscle and suggest that its use at pharmacological doses should be avoided by individuals with dysferlinopathies. ER -