Treating muscle and brain alike: benefits of GSK3 inhibition inmdxmice

Abstract

SummaryIn addition to progressive muscle wasting and weakness, many patients living with Duchenne muscular dystrophy (DMD) will experience cognitive decline, which further compromises their quality of life. Here, we questioned whether inhibiting glycogen synthase kinase 3 (GSK3) in the DBA/2Jmdxmouse model of DMD could benefit both muscle and brain health. Short-term treatment with the clinically advanced GSK3 inhibitor, tideglusib, reduced skeletal and cardiac muscle necrosis, improving force production and diastolic function. Similar benefits were found when GSK3 inhibition via lithium supplementation was combined with voluntary wheel running. In the brain, GSK3 was found to be overactive in the hippocampus frommdxmice; and inhibiting GSK3 improved cognitive function. Further, this result was associated with reduced beta-secretase activity and increased clearance of β-amyloid. Altogether, our findings reveal GSK3 inhibition as a potential therapy for DMD – one aimed at enhancing muscle and brain health and overall quality of life.HighlightsTideglusib treatment lowered muscle necrosis and improved cardiac and skeletal muscle functionCombined effects of voluntary wheel running and lithium supplementation improved skeletal and cardiac muscle function despite running significantly lessGSK3 inhibition shifts brain biochemistry away from an Alzheimer’s-like pathology inmdxmice and improves cognitive functionGSK3 inhibition can treat both muscles and brain and could potentially improve the quality of life of those living with DMD