Effect of Ibuprofen on Skeletal Muscle of Dysferlin-Null Mice

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 -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, 0.67-8.2g/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.

Angiotensin II receptor blocker losartan exacerbates muscle damage and exhibits weak blood pressure-lowering activity in a dysferlin-null model of Limb-Girdle muscular dystrophy type 2B

“…Active sites of muscle necrosis and bulk inflammation in both muscle groups was minor (<10%; S2B Fig ), yet reduced in rectus femoris muscles of HFD-fed mice. Despite obvious histological changes, plasma CK levels (a bi-phasic marker of muscle damage) were unaffected ( S2C Fig ), as published by others in dysferlin-null animals [25]. Together, these data show an exacerbation of muscle wasting by losartan in both the triceps brachii and quadriceps (rectus femoris), two muscle groups severely affected by LGMD2B [8,9].…”

“…Based on the dramatic changes in muscle size in losartan-treated animals, one can anticipate changes in muscle weights; however plasma CK (a commonly used marker of muscle damage in both clinical and preclinical muscle disease) was not affected in the present study, as shown by others [25]. In mdx mice, reduced plasma CK and improved lipid profiles (reduced TG, increased HDL-C) were correlated with reduced muscle damage and pathology following chronic losartan treatment [13].…”

Development of muscular dystrophy in a CRISPR-engineered mutant rabbit model with frame-disrupting ANO5 mutations

“…There are many examples in the literature that the severity of disease could be affected by genetic backgrounds and/or species. For example, mdx mice, a widely used mouse model of Duchenne muscular dystrophy (DMD), have much milder pathology as compared with DMD patients 20 ; the severity of muscular dystrophy in dysferlin-null mice depends on their genetic background 21 ; a common disease-associated missense mutation in α-sarcoglycan fails to cause muscular dystrophy in mice 22 . Studies have shown that genetic modifiers may affect the disease outcomes in DMD and dysferlinopathy 23 , 24 .…”

Ibuprofen, Flurbiprofen, Etoricoxib or Paracetamol Do Not Influence ACE2 Expression and Activity In Vitro or in Mice and Do Not Exacerbate In-Vitro SARS-CoV-2 Infection

“…Male C57Bl/6J mice (age of ~12 weeks at the start of the study) were purchased from Charles River (Sulzfeld, Germany): 32 total, 8 mice per group. This mouse strain was selected because there are a relatively large number of studies on ibuprofen in C57Bl/6J mice and therefore it is easier to choose relevant ibuprofen doses [35,36]. The choice of gender was based on the suggestion that men appear to be more affected by COVID-19 than women [37][38][39].…”