A Slc5a6-deficient mouse model reveals metabolically driven cardiomyopathy with therapeutic potential for...

Area of Science:

• Cardiovascular Biology
• Metabolic Disorders
• Genetics

Background:

• The sodium-dependent multivitamin transporter (SLC5A6) is crucial for cellular uptake of biotin and pantothenic acid, vital energy metabolism cofactors.
• Mutations in SLC5A6 have been linked to early-onset dilated cardiomyopathy (DCM).

Purpose of the Study:

• To investigate the pathogenic link between SLC5A6 dysfunction, vitamin deficiency, and cardiomyopathy development.
• To evaluate the therapeutic potential of vitamin supplementation in a relevant preclinical model.

Main Methods:

• Generated a cardiac-specific SLC5A6 knockout (Slc5a6cKO) mouse model.
• Assessed cardiac function using MRI and ECG, and analyzed cardiac pathology, Coenzyme A synthesis, and mitochondrial metabolism.
• Evaluated the impact of early-life vitamin supplementation on cardiac phenotype and survival.

Main Results:

• Slc5a6cKO mice exhibited progressive cardiac dysfunction, hypertrophy, fibrosis, impaired Coenzyme A synthesis, and premature death.
• Mitochondrial metabolic disruption and extracellular matrix changes were observed early, preceding overt cardiac dysfunction.
• Preconception vitamin supplementation completely prevented cardiac pathology and mortality in Slc5a6cKO mice, mirroring a positive clinical outcome in a treated patient.

Conclusions:

• Establishes a direct role for SLC5A6-mediated vitamin transport in maintaining cardiac health and mitochondrial function.
• Demonstrates that vitamin deficiency is a contributing factor to cardiomyopathy pathogenesis.
• Supports early vitamin supplementation as a potential therapeutic strategy for SLC5A6-related metabolic cardiomyopathies.