Elimination of fukutin reveals cellular and molecular pathomechanisms in muscular dystrophy-associated heart failure

Area of Science:

• Cardiovascular Biology
• Muscle Physiology
• Genetic Disorders

Background:

• Heart failure is a primary cause of mortality in muscular dystrophy patients.
• The precise molecular mechanisms underlying muscular dystrophy-associated cardiomyopathy are not fully understood.

Purpose of the Study:

• To elucidate the molecular pathogenesis of cardiomyopathy in mice lacking the fukutin (Fktn) gene, causative for Fukuyama muscular dystrophy.
• To investigate the role of fukutin in cardiac function and myocyte integrity.

Main Methods:

• Generation and analysis of mice with cardiac-specific Fktn elimination.
• Assessment of α-dystroglycan glycosylation and dystrophin-glycoprotein complex integrity.
• Evaluation of cardiac function, myocyte contractility, and Golgi-microtubule networks.
• Investigation of signaling pathways including Akt and MEF2-histone deacetylase axis.

Main Results:

• Cardiac Fktn elimination reduced sarcolemmal α-dystroglycan glycosylation and dystrophin-glycoprotein complex proteins.
• Cardiac dysfunction manifested in later adulthood, indicating membrane fragility is not the sole cause.
• Fktn-deficient mice showed vulnerability to hypertrophic stress with altered Akt and MEF2 signaling.
• Acute Fktn loss led to severe cardiac dysfunction, mortality, myocyte contractile issues, and Golgi-microtubule disarray, partially improved by colchicine.

Conclusions:

• Fukutin is critical for maintaining myocyte physiology and preventing heart failure in muscular dystrophy.
• Disruption of Golgi-microtubule networks contributes to cardiac dysfunction.
• These findings suggest potential therapeutic strategies targeting fukutin's role in myocyte health.