Harnessing the Sirtuin 6-Thyroid Hormone cross talk to counteract the progression of the Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD) is a fatal genetic disease. Muscle weakness is the principal symptom that appears early between ages 2 and 6. The affected children show difficulties in jumping, running, and walking, and an impairment of heart and respiratory muscles with death occurring during the 20s-30s. Due to the severity of the disease, there is an urgent need to discover potential pharmacological targets to slow muscle weakness. In the last decades, researchers focused their efforts on identifying key determinants of muscle physiology that if altered can favour DMD progression. Thyroid Hormone (TH) is a critical endocrine regulator of muscle physiology. The tight control of TH status in skeletal muscle is essential for muscle growth, function and maintenance and its alteration is a leading cause of myopathies. Recently, there is a great attention on the role of SIRT6 as key transcriptional regulator involved in several diseases including DMD, because of its involvement in the modulation of the expression of genes critical for muscle mass turnover. Our preliminary data suggest that high SIRT6 activity in DMD may be causative of a TH reduction. Our hypothesis is that during the DMD pathology enhanced SIRT6 expression reduces the TH levels and thus impairs the proper regeneration of skeletal muscle, thus worsening the progression of the disease. Our goal is to shed light on SIRT6 as new target for DMD treatment and pave the way to the use of SIRT6 inhibitors as combinatorial therapies to attenuate muscle degeneration in DMD patients.