Skeletal Muscle MicroRNAs as Key Players in the Pathogenesis of Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, for which, to date, no effective treatment to ameliorate the clinical manifestations is available. The long-standing view of ALS as affecting only motor neurons has been challenged by the finding that the skeletal muscle plays an active role in the disease pathogenesis and can be a valuable target for therapeutic strategies. In recent years, non-coding RNAs, including microRNAs, have emerged as important molecules that play key roles in several cellular mechanisms involved in the pathogenic mechanisms underlying various human conditions. In this review, we summarize how the expression of some microRNAs is dysregulated in the skeletal muscle of ALS mouse models and patients. Shedding light on the mechanisms underlying microRNAs dysregulation in the skeletal muscle could clarify some of the processes involved in the pathogenesis of ALS and especially identify new promising therapeutic targets in patients.

Keywords: amyotrophic lateral sclerosis; gene expression signature; microRNA; molecular biomarkers; molecularly targeted therapies; skeletal muscle.

Figure 1

miR-206 signaling in slow and fast twitch muscles. miR-206 levels are higher in slow muscles than in fast ones and this basal expression makes the slow-twitch muscles more resistant to denervation. During the denervation process, typical of ALS disease, in fast-twitch muscles miR-206 levels increase to sustain re-innervation. Acting directly on microRNAs in the skeletal muscle could be a feasible therapeutic strategy aimed at making the muscle more resistant to denervation, increasing the responses that promote re-innervation (figure modified from https://smart.servier.com/). The green arrows link the different responses of slow- and fast-twitch muscles to the different miR-206 expression levels; the orange arrows show the signaling cascade in fast-twitch muscle following denervation; ↑: increased levels; ↓: decreased levels.