miR-10a-5p and miR-10b-5p restore colonic motility in aged mice.

Background: We previously identified miR-10b-5p as a key regulator of gastrointestinal (GI) motility through its essential role in the development and function of interstitial cells of Cajal (ICC), the pacemaker cells of the gut. Loss of miR-10b-5p in ICC impairs intestinal motility and contributes to constipation, a common condition in the elderly. Notably, miR-10b-5p is co-expressed with its paralog, miR-10a-5p, in ICC.

Aim: To investigate the roles of miR-10a-5p and miR-10b-5p in age-associated intestinal dysmotility and assess the therapeutic potential of restoring their expression.

Methods: We employed aged mice, and single and double knockout (KO) models, and human plasma and colon samples across age groups. GI and colonic transit, ICC network integrity, and expression levels of miR-10a/b-5p were evaluated. Additionally, we tested whether treatment with their microRNA mimics could restore GI motility in aged mice.

Results: Aged mice exhibited delayed GI and colonic transit, reduced fecal output, and diminished expression of miR-10a-5p and miR-10b-5p, which peaked during late embryonic and early postnatal stages and declined with age. This decline paralleled ICC network deterioration in the colon. All KO models exhibited impaired motility and ICC loss, with KO mice displaying more severe phenotypes than KO mice. Double KO mice demonstrated growth retardation and reduced survival, with homozygous mutants living only up to 3 months. Treatment of aged mice with miR-10a-5p and miR-10b-5p mimics encapsulated in jetPEI significantly improved GI and colonic motility. Successful delivery to the gut, including the colon, was confirmed. In human samples, both miR-10a/b-5p and KIT expression decreased with age.

Conclusion: miR-10a-5p and miR-10b-5p are essential for ICC maintenance and colonic motility, and their age-related decline contributes to GI dysmotility in both mice and humans. Restoring their levels offers a promising therapeutic strategy for treating age-related constipation and other motility disorders.