Myotonic dystrophy type I (DM1) exhibits distinctive disease specific phenotypes and the accelerated onset of a spectrum of age-associated pathologies. In DM1, dominant effects of expanded CUG repeats result in part from the inactivation of the muscleblind-like (MBNL) proteins. To test the role of MBNL3, we deleted Mbnl3 exon 2 (Mbnl3ΔE2) in mice and examined the onset of age-associated diseases over 4 to 13 months of age. Accelerated onset of glucose intolerance with elevated insulin levels, cardiac systole deficits, left ventricle hypertrophy, a predictor of a later onset of heart failure and the development of subcapsular and cortical cataracts is observed in Mbnl3ΔE2 mice. Retention of embryonic splice isoforms in adult organs, a prominent defect in DM1, is not observed in multiple RNAs including the Insulin Receptor (Insr), Cardiac Troponin T (Tnnt2), Lim Domain Binding 3 (Ldb3) RNAs in Mbnl3ΔE2 mice. Although rare DM1-like splice errors underlying the observed phenotypes cannot be excluded, our data in conjunction with the reported absence of alternative splice errors in embryonic muscles of a similar Mbnl3ΔE2 mouse by RNA-seq studies, suggest that mechanisms distinct from the adult retention of embryonic splice patterns may make important contributions to the onset of age-associated pathologies in DM1.

Patients with stage 5 chronic kidney disease (CKD5D) have a higher risk of developing neurocognitive deficits. Stroke, cervical carotid artery disease (CCAD), and intracranial atherosclerotic disease (ICAD) are causes of such deficits in CKD5D. Chronic inflammation from renal failure elevates risk for these diseases through oxidative stress and vascular dysfunction. The adverse impact on the carotid and intracranial vasculatures contributes to the multifactorial pathophysiology of stroke. Eleven plasma biomarker levels in patients with CKD5D (n = 97) and healthy controls (n = 17-50) were measured using sandwich enzyme-linked immunosorbent assay (ELISA) method. Of the 97 patients with CKD5D, 24 had CCAD, 19 had ICAD, and 23 had acute stroke. Elevations in NACHT, LRR, and PYD domains-containing protein 3 (NALP3) levels in patients with CKD5D (+)CCAD (1.80 ± 0.11 ng/mL) compared to patients with (−)CCAD (1.55 ± 0.08 ng/mL) were statistically significant ( P = .0299). Differences in D-dimer levels were also found to be statistically significant ( P = .0258) between CKD5D (+)stroke (1.83 ± 0.42 μg/mL) and (−)stroke (0.89 ± 0.13 μg/mL) groups. The ages of the (+) neurovascular disease groups were found to be significantly elevated compared to the (−) neurovascular disease groups ( P = .0002 carotid AD; P < .0001 ICAD; P = .0157 stroke). D-dimer levels were positively correlated with age in CKD5D ( P = .0375). With the possible exception of NALP3 for CCAD, profiling levels of specific biomarkers for risk stratification of neurovascular diseases in the CKD5D population warrants further investigation.