The microRNA, miR-133b, functions to slow Duchenne muscular dystrophy pathogenesis

Abstract

Duchenne muscular dystrophy (DMD) is characterized by progressive degeneration of skeletal muscles. To date, there are no treatments available to slow or prevent the disease. Hence, it remains essential to identify molecular factors that promote muscle biogenesis since they could serve as therapeutic targets for treating DMD. While the muscle enriched microRNA, miR-133b, has been implicated in the biogenesis of muscle fibers, its role in DMD remains unknown. To assess the role of miR-133b in DMD-affected skeletal muscles, we genetically ablated miR-133b in the mdx mouse model of DMD. In the absence of miR-133b, the tibialis anterior muscle of juvenile and adult mdx mice is populated by small muscle fibers with centralized nuclei, exhibits increased fibrosis, and thickened interstitial space. Additional analysis revealed that loss of miR-133b exacerbates DMD-pathogenesis partly by altering the number of satellite cells and levels of protein-encoding genes, including previously identified miR-133b targets as well as genes involved in cell proliferation and fibrosis. Altogether, our data demonstrate that skeletal muscles utilize miR-133b to mitigate the deleterious effects of DMD.

Micro (mRNA) molecules could pack a big punch in the fight against neuromuscular disease

“…Micro-RNAs (miR) are short, non-encoding RNAs that have emerged as important post-transcriptional regulators of many genes including those that control satellite cell activity, muscle growth and regeneration (Forcina et al 2019). In this issue of The Journal of Physiology, Taetzsch et al (2021) describe for the first time the temporal changes in muscle-specific miR-133b throughout the pathogenesis of murine (mdx) DMD and the effect of miR-133b deletion on the mdx phenotype. Although it is the 'gold-standard' animal model of DMD because of its genetic homology to human DMD, the mdx mouse has a peculiar phenotype making translational research challenging.…”

“…In this issue of The Journal of Physiology , Taetzsch et al . (2021) describe for the first time the temporal changes in muscle‐specific miR‐133b throughout the pathogenesis of murine ( mdx ) DMD and the effect of miR‐133b deletion on the mdx phenotype. Although it is the ‘gold‐standard’ animal model of DMD because of its genetic homology to human DMD, the mdx mouse has a peculiar phenotype making translational research challenging.…”

“…address this aspect by investigating multiple time points and importantly show that miRNA‐133b is robustly expressed in mdx muscles, and significantly more so in the severe compared to the remission phase of mdx MD (Taetzsch et al . 2021). Genetic knockout of miR‐133b had little effect on wild‐type muscles, yet it exacerbated MD in mdx mice, suggesting that miR‐133b attenuates the severity of DMD‐associated myopathy (Taetzsch et al .…”

“…Genetic knockout of miR‐133b had little effect on wild‐type muscles, yet it exacerbated MD in mdx mice, suggesting that miR‐133b attenuates the severity of DMD‐associated myopathy (Taetzsch et al . 2021). Taetzsch et al .’s data highlight that miR‐133b is crucial for mediating the molecular response to damage which facilitates repair and regeneration of skeletal muscle and could thus be targeted through genetic or pharmacological intervention as a treatment for DMD.…”

Therapeutic potential of miRNAs in Duchenne muscular dystrophy and other neuromuscular diseases

“…Overall, this study established a definitive role for miR‐133b as a part of the body's compensatory mechanism during muscle repair after acute injury (Taetzsch et al . 2021). miR‐133b is directly involved in muscle repair by stimulating satellite cells and can suppress pathways involved in inflammation and fibrosis.…”