microRNA-22 Inhibition Stimulates Mitochondrial Homeostasis and Intracellular Degradation Pathways to Prevent Muscle Wasting

MicroRNA-22 (miR-22) is a negative regulator of mitochondrial biogenesis as well as lipid and glucose metabolism in metabolically active tissues. Silencing miR-22 holds promise as a potential treatment of obesity and metabolic syndrome as it restores metabolic capacity – enhancing oxidative metabolism – and reduces ectopic fat in chronic obesity, a driver of impaired metabolic flexibility and muscle mass loss. Intramuscular adipose accumulation and defective mitochondrial function are features associated with obese-mediated muscle atrophy and hallmarks of neuromuscular disorders such as Duchenne muscular dystrophy. Therefore, miR-22 could represent a compelling molecular target to improve muscle health across various muscle-wasting conditions. This study describes a pharmacological strategy for inhibition of miR-22 in skeletal muscle by employing a mixmer antisense oligonucleotide (ASO, anti-miR-22). Administration of the ASO in a mouse model of obesity positively modulated myogenesis, while it protected dystrophic mice from muscle function decline enhancing fatigue resistance and limiting pathological fibrotic remodeling. Mechanistically, we show that anti-miR-22 treatment promotes derepression of genes involved in mitochondrial homeostasis favoring oxidative fiber content regardless of the disease model, thus promoting a more resilient phenotype. Furthermore, we suggest that miR-22 inhibition increases autophagy by transcriptional activation of multiple negative regulators of mammalian target of rapamycin (mTOR) signaling to decrease immune infiltration and fibrosis. These findings position miR-22 as a promising therapeutic target for muscle-wasting conditions and support its potential to restore muscle health. Overall design: Bulk RNA-seq of gastrocnemius muscles from 30-week-old diet-induced obese C57BL/6J mice (high fat diet) after a 14-weeks-long treatment either with saline solution or an anti-miR-22 antisense oligonucleotide.