MechanomiR Screen Can Identify Deregulated Players In Muscle Degeneration

In a new study entitled “Genome-wide Mechanosensitive MicroRNA (MechanomiR) Screen Uncovers Dysregulation of their Regulatory Networks in the mdm Mouse Model of Muscular Dystrophy” researchers performed a genome-wide study to identify whether mechanosensitive microRNAs are deregulated and contribute to muscular dystrophies pathogenesis. The study was published in The Journal of Biological Chemistry.

Muscular dystrophies (MDs) are a group of disorders characterized by loss of skeletal muscle mass and function, leading to patients’ immobility and, in some cases, problems in breathing or swallowing. While the main cause of MD is the lack of function of structural proteins (such as dystrophin in the cases of Becker and Duchene MDs), defects in mechanotransduction have also been suggested to play a role in MDs pathogenesis.

Mechanotransduction is a process whereby cells translate the way they sense their physical environment into biochemical signals, such as activating certain signaling pathways, and is a vital process for cells and tissues’ homeostasis. For instance, in Duchene muscular dystrophy, (the most common MD in children with patients surviving only till their 20s) muscle degeneration is caused by loss of forces connecting the cytoskeletal to the extracellular matrix. Previous studies showed that this resulted in increased expression of the inflammatory cytokines and changes in calcium concentrations within cells. Hence, studying how mechanotransduction impacts muscular dysfunction may translate into important clinical findings.

Here, authors wanted to understand how changes in mechanotransduction lead to muscular dysfunction. Specifically, the team focused on dysregulated-microRNA pathways (microRNAs are small regulatory RNAs that regulate gene expression), since microRNAs perturbed expression is often associated with skeletal muscle diseases, including MDs.

To this end, they performed a whole-genome analysis for mechanosensitive microRNAs (MechanomiR) and determined whether their deregulated expression contributed to the progression of MD. Researchers performed their study in both mechanically stretched and un-stretched diaphragm muscles from WT and mdm (muscular dystrophy with myositis) mice, the latter a model of human tibial MD.

The results demonstrated that in both mice models, mechanical stretch significantly altered microRNAs’ expression profile. Notably, the authors discovered one family of microRNAs, the highly expressed let-7 family, whose expression was the opposite between WT and mdm mice. Furthermore, the team discovered that two let-7 family members (let-7e-5p and miR-98-5p) and respective target genes lead to activation of TGF-β1/SMAD signaling pathway in the diaphragm of mdm mice, contributing to disease progression.

“Overall, we uncovered a role for mechanomiR in skeletal muscle function, and propose that dysregulation of mechanomiRs may be associated with development of human skeletal muscle diseases including MD”, the authors conclude in their study.