RT Journal Article
SR Electronic
T1 Effect of Ibuprofen on Skeletal Muscle of Dysferlin-Null Mice
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 409
OP 419
DO 10.1124/jpet.117.244244
VO 364
IS 3
A1 Alyssa F. Collier
A1 Jessica Gumerson
A1 Kimmo Lehtimäki
A1 Jukka Puoliväli
A1 Jace W. Jones
A1 Maureen A. Kane
A1 Sankeerth Manne
A1 Andrea O’Neill
A1 Hillarie P. Windish
A1 Toni Ahtoniemi
A1 Bradley A. Williams
A1 Douglas E. Albrecht
A1 Robert J. Bloch
YR 2018
UL http://jpet.aspetjournals.org/content/364/3/409.abstract
AB 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.