A Slc5a6 Deficient Mouse Model Reveals a Metabolically Driven Dilated Cardiomyopathy with Therapeutic Potential for Vitamin-Based Intervention

Abstract

Background and AimsThe sodium-dependent multivitamin transporter, encoded by SLC5A6, mediates cellular uptake of the vitamins, biotin and pantothenic acid, both of which are essential cofactors for energy metabolism. Here, we report two families with SLC5A6 mutations presenting with early-onset dilated cardiomyopathy (DCM). To investigate the link between vitamin deficiency and DCM, we generated a novel cardiac-specific Slc5a6 knockout (Slc5a6cKO) mouse model and tested the therapeutic potential of vitamin supplementation. MethodsCardiac function in Slc5a6cKO mice was assessed by cardiac magnetic resonance imaging and ECG measurements. Histological, biochemical, and proteomic analyses were conducted to identify structural and metabolic changes. The impact of dietary biotin and pantothenic acid supplementation on disease progression was evaluated. ResultsSlc5a6cKO mice developed progressive cardiac dysfunction, manifesting as DCM with cardiac dilation, cardiomyocyte hypertrophy, fibrosis, impaired Coenzyme A synthesis, and metabolic imbalance, culminating in premature death by 26 weeks. Proteomic analysis revealed early mitochondrial metabolic disruption and extracellular matrix protein upregulation at 8 weeks, preceding overt cardiac dysfunction. Strikingly, vitamin supplementation from preconception onwards, prevented the cardiac phenotype, preserving cardiac structure, function, morphology and survival. This parallels the clinical outcome in one patient who received early vitamin treatment, compared to another who required a heart transplant following delayed vitamin treatment. ConclusionsThis study establishes a direct link between SLC5A6-mediated vitamin transport, mitochondrial function, and cardiac health. It highlights how vitamin deficiency contributes to DCM pathogenesis and supports early vitamin supplementation as a potential therapeutic strategy for metabolic cardiomyopathies. Translational perspectiveThis study highlights the therapeutic potential of vitamin supplementation in treating dilated cardiomyopathy (DCM) caused by mitochondrial abnormalities. Using a cardiac-specific Slc5a6 knockout mouse model, we demonstrated that deficiencies in key vitamins, biotin and pantothenic acid, impair mitochondrial energy metabolism, leading to DCM progression. Remarkably, vitamin supplementation preserved cardiac function, morphology, and survival, suggesting that restoring vitamin levels could be a promising therapeutic strategy for DCM and other cardiomyopathies linked to metabolic deficiencies. These findings could inform newborn screening programmes and clinical approaches for treating mitochondrial-related cardiac diseases by targeting specific vitamin deficiencies. Key QuestionWhat is the underlying molecular cause of early-onset dilated cardiomyopathy in patients with SLC5A6 mutations, and can insights from a cardiac-specific knockout mouse model reveal potential metabolic mechanisms and therapeutic strategies involving vitamin supplementation? Key FindingCardiac-specific deletion of Slc5a6 in mice caused early mitochondrial dysfunction, metabolic derangement, and progressive dilated cardiomyopathy. Strikingly, early and continuous supplementation with biotin and pantothenic acid completely preserved cardiac structure, function, and survival, paralleling successful outcomes in patients treated early. Take Home MessageThis study establishes a mechanistic link between SLC5A6 mutations, vitamin deficiency and mitochondrial abnormalities as a cause of dilated cardiomyopathy. Early vitamin supplementation prevents disease onset, highlighting the potential of targeted vitamin therapy in metabolic cardiomyopathies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/658273v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@cf8e8corg.highwire.dtl.DTLVardef@97c74borg.highwire.dtl.DTLVardef@9d0e41org.highwire.dtl.DTLVardef@112eb77_HPS_FORMAT_FIGEXP M_FIG C_FIG