TNF-α-Induced microRNAs Control Dystrophin Expression in Becker Muscular Dystrophy.

The amount and distribution of dystrophin protein in myofibers and muscle is highly variable in Becker muscular dystrophy and in exon-skipping trials for Duchenne muscular dystrophy. Here, we investigate a molecular basis for this variability. In muscle from Becker patients sharing the same exon 45-47 in-frame deletion, dystrophin levels negatively correlate with microRNAs predicted to target dystrophin. Seven microRNAs inhibit dystrophin expression in vitro, and three are validated in vivo (miR-146b/miR-374a/miR-31). microRNAs are expressed in dystrophic myofibers and increase with age and disease severity. In exon-skipping-treated mdx mice, microRNAs are significantly higher in muscles with low dystrophin rescue. TNF-α increases microRNA levels in vitro whereas NFκB inhibition blocks this in vitro and in vivo. Collectively, these data show that microRNAs contribute to variable dystrophin levels in muscular dystrophy. Our findings suggest a model where chronic inflammation in distinct microenvironments induces pathological microRNAs, initiating a self-sustaining feedback loop that exacerbates disease progression.

Associations of sex, breed, and age with cervical vertebral compressive myelopathy in horses: 811 cases (1974-2007).

OBJECTIVE: To determine sex, breed, and age distributions in a population of horses with cervical vertebral compressive myelopathy (CVCM), compared with contemporaneous control horses. DESIGN: Retrospective case-control study. ANIMALS: 811 horses with CVCM and 805 control horses. PROCEDURES: The Veterinary Medical Database was searched to identify horses with CVCM and contemporaneous control horses registered between July 1974 and August 2007. Admission date, admitting institution, sex, breed, age at the time of registration in the database, weight, and discharge status (alive, died, or euthanized) were recorded for each case and control horse. RESULTS: On the basis of results of multivariable logistic regression analysis, geldings and sexually intact males had a significantly higher likelihood of having CVCM than females (odds ratio [OR], 2.0 [95% confidence interval, 1.5 to 2.6]; and OR, 2.4 [95% confidence interval, 1.8 to 3.2], respectively). Thoroughbreds, Tennessee Walking Horses, and Warm-bloods were overrepresented in the CVCM group, compared with Quarter Horses. Horses that ranged from < 6 months to < 7 years of age had significantly higher odds of having CVCM, compared with horses > or = 10 years of age. CONCLUSIONS AND CLINICAL RELEVANCE: Sex, breed, and age predilections were detected in horses with CVCM. Improved understanding of these factors will aid clinical recognition of the disease in groups that may have a high prevalence of CVCM or were previously not recognized to be commonly affected. The results may also stimulate future investigations to further delineate etiopathogenesis, such as breed-related genetic causality.