Supplementary Materials Data S1

Supplementary Materials Data S1. compared with vehicle\treated making it through mice. DKO center weight, both only and normalized to tibial size, didn’t differ with ifetroban treatment (5.000.57?g/mm for automobile and 4.930.51?g/mm with ifetroban). Likewise, in second\era mdx/mTR(?/?) mice, a style of DMD with shortened telomeres,23 treatment with ifetroban improved 6\month success from 43% to 100%, and improved the 3\month cardiac index, mainly due to increased stroke quantity (Shape?1C and ?and11D). Open up in another window Shape 1 Thromboxane\prostanoid receptor (TPr) antagonism improved success and Pefloxacin mesylate cardiac result in 2 Duchenne muscular dystrophy (DMD) mouse versions. A, Success of dual knockout (DKO) mice towards the predetermined 10\week period point. Curves had been likened by Mantel Cox log\rank check, and quantity/sex of mice in each combined group are shown. Six DKO mice, including both automobile\ and ifetroban\treated mice, had been accidentally positioned on high\fats breeder chow for a number of weeks that resulted in improved putting on weight and health weighed against previous decades; Pefloxacin mesylate these mice had been omitted from success evaluation. B, Echocardiography evaluation from the DKO cohort. n=10 wildtype (WT) and 5 to 6 as demonstrated per DKO group (remaining ventricular measurements cannot be acquired for 1 automobile\treated mouse). The mean and regular error of every measurement are demonstrated, and evaluations between automobile\treated and ifetroban\treated DKO had been created by 2\tailed check. C, Survival and (D) echocardiography of male mdx/mTR mice. Because so few vehicle\treated mice survived to 6?months, echocardiographs are from 3?months of age; echocardiographs from 3\month\old WT male mice are shown for Cish3 comparison. n=8 to 10 WT, n=5 vehicle\treated, and n=4 ifetroban\treated mdx/mTR. Statistical analysis of groups was performed as in (A and B). CI indicates cardiac index (cardiac output normalized to body surface area); FS, fractional shortening; SV, stroke volume. While the 10\week\old DKO mice had profound fibrosis of the diaphragm and fibrosis/necrosis of the TA, which did not improve with TPr antagonism (Figure?2A and ?and2B),2B), they did not yet display the diffuse myocardial fibrosis characteristic of DMD (Figure?2C). Furthermore, the severe kyphosis in both DKO treatment groups prevented intubation for invasive hemodynamics, while the high spontaneous mortality of DKO and mdx/mTR mice precluded tissue collection and made survivor bias likely. Therefore, to more completely examine the effects of TPr antagonism on the MD cardiac Pefloxacin mesylate phenotype, we used dSG KO mice, which contain a mutation associated with limb\girdle MD type 2F and develop a dilated cardiomyopathy with diffuse fibrosis, similar to individuals with other forms of MD.25 dSG KO mice had overall better 6\month survival (90%) compared with the other genotypes used, which improved to 100% with ifetroban treatment (Figure?3A). Noticeably, the few deaths in dSG KO mice occurred either during or just following placement of in\cage running wheels before 3\ and 6\month echocardiographs (Figure?3A); this corresponds with initial reports of sudden cardiac death in these mice following forced treadmill exercise.25 At 6?months, heart weights and ratios were not significantly increased from WT, although Pefloxacin mesylate dSG KO mice exhibited pseudohypertrophy of hind leg muscles, similar to patients with DMD, which led to an elevated body weight (Table). Physical parameters of dSG KO, DKO, and mdx/mTR mice are summarized in the Table. Open in a separate window Figure 2 Double knockout (DKO) histology. A, Thromboxane\prostanoid receptor (TPr) antagonism does not improve skeletal muscle fibrosis. Shown is diaphragm (top) at 40 and tibialis anterior (TA, bottom) at 20, stained with Masson trichrome. Scale bar=50?m. Fibrosis (blue) was quantitated in NIS elements and averaged from 4 fields per mouse. Groups were compared using 2\way ANOVA/Holm\Sidak. The mean and standard error is shown. B, TPr antagonism does not prevent skeletal muscle.