Abstract
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.
Footnotes
- Received August 2, 2017.
- Accepted December 21, 2017.
↵1 A.F.C. and J.G. contributed equally to this work.
↵2 Current affiliation: Program in Physical Therapy, Washington University School of Medicine, St. Louis, Missouri.
↵3 Current affiliation: National Eye Institute, Bethesda, Maryland.
This work has been supported in part by the University of Maryland Baltimore, School of Pharmacy Mass Spectrometry Center [SOP1841-IQB2014], by a traineeship to J.G. from the National Institutes of Health [Grant T32 AR 007592, Dr. M. Schneider, P.I.], by a generous donation by the Williams family, and by the Kahlert Foundation, the Jain Foundation, and grants to R.J.B. from the Jain Foundation and the National Institutes of Health [Grant RO1 AR064268].
- Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics