Study of non coding RNAs affecting mitochondrial morphology and functionality in skeletal muscle

Skeletal muscle is one of the most dynamic and plastic tissues of the human body and contributes significantly to multiple functions. Emerging evidence suggests that non coding RNAs, important regulators of gene expression, are critical for skeletal muscle physiology and pathology. From previous results it is known that some specific ncRNAs, such as microRNAs (miRNAs) and long non coding RNAs (lncRNAs), are differentially expressed during skeletal muscle atrophy and myoblast differentiation. Among the lncRNA, we further investigate the lncRNA Gas5 that result upregulated specifically in muscle of ALS mouse, and it is a predicted target of miR-30 family, an important microRNA family involved in muscle differentiation and atrophy. Interestingly, we demonstrated that miR-30c and miR-30e can downregulate Gas5 isoform 5 and isoform 6. We elucidated Gas5 isoforms expression in different atrophy condition (denervation-, starvation-induced atrophy and ALS muscle), Gas5 results highly expressed only in skeletal muscle of terminally ill mouse model of ALS. Using C2C12 cells we overexpressed Gas5 transcript isoforms and performed transcriptional profiling showing this lncRNA promotes muscle atrophy and can impact on mitochondria and endoplasmic reticulum. Mitochondria play a crucial role in skeletal muscle, they are highly dynamic organelles, which undergo frequent structural and metabolic changes to fit cellular demand. We focus on mitochondrial functionality demonstrating that Gas5 induces fragmentation, apoptosis and reduce fatty acid metabolism (main source of energy for skeletal muscle).