Treating Smn2B/− spinal muscular atrophy (SMA) mice with commercially approved metabolism-targeting interventions leads to improved disease phenotypes

Abstract Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular condition that is increasingly recognized as a multi-systemic disorder in which metabolic dysfunction plays a central role. Reframing SMA pathology from a neurocentric to a metabolic perspective reveals abnormalities in metabolic tissues such as skeletal muscle, liver, pancreas and adipose tissue, including insulin resistance, hepatic steatosis, dyslipidemia and circadian disruption. Although currently approved disease-modifying therapies significantly improve survival and motor function, they do not adequately address peripheral and metabolic pathologies, underscoring the need for the development of complementary strategies aimed at modulating metabolic homeostasis. We used our previously published work aimed at combining bioinformatics and drug repositioning strategies to identify three metabolism-targeting compounds with strong translational potential: pioglitazone, melatonin and insulin. We therefore assessed their therapeutic potential and activities in SMA Smn 2B/- mouse and C. elegans models. We observed that albeit to different extents, all three drugs improved various behavioural, molecular and/or histological pathological phenotypes in SMA mice and worms such as survival, weight, motor function, muscle size, spinal cord health and hepatic lipid accumulation. Melatonin, which had the most significant effect on survival, showed activity in several tissues, impacting molecular effectors involved in circadian rhythm, glucose metabolism, mitochondria biogenesis and browning of white adipose tissue. Together, these findings position metabolism at the forefront of targets for SMA treatments and provide strong rationale for exploring metabolism-targeted second-generation therapies to complement currently approved disease-modifying treatments.