Phillips, H. M. | bioRxiv Science

bioRxiv2025

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

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

genetics↗

bioRxiv2021

Iba1+ cell density and morphology classification at postnatal day 10 in four hippocampal subregions of female and male C57BL/6J mice

Microglia, the resident immune cells of the brain, support normal brain function and the brains response to disease and injury. The hippocampal dentate gyrus (DG) is an area of microglial study due to its central role in many behavioral and cognitive functions. Interestingly, microglia and related cells are distinct in female vs. male rodents, even in early life. Indeed, postnatal day (P)-dependent sex differences in number, density, and morphology of microglia have been reported in certain hippocampal subregions at specific ages. However, sex differences in the DG have not yet been assessed at P10, a rodent developmental time point translationally relevant to human term gestation. To address this knowledge gap, Iba1+ cells in the DG (which are enriched in the Hilus and Molecular Layer) in female and male C57BL/6J mice were analyzed for their number (via stereology) and density (via stereology and via sampling). Next, Iba1+ cells were classified into published morphology categories. Finally, the percent of Iba1+ cells in each morphology category was multiplied by total cell number to generate a total number of Iba1+ cells in each morphological category. Results show no sex difference in Iba1+ cell number, density, or morphology in the P10 Hilus or Molecular Layer. The lack of sex difference in Iba1+ cells in P10 DG using commonly-employed methodologies (sampling, stereology, morphology classification) provides a baseline from which to interpret microglia changes seen after injury. HIGHLIGHTSO_LISex differences in Iba1+ cells were assessed in the dentate gyrus (DG) of P10 mice C_LIO_LIIba1+ cells were assessed in DG microglia-rich subregions: Hilus and Molecular Layer C_LIO_LIBoth stereology and sampling approaches were used to quantify Iba1+ cells C_LIO_LINo sex difference found in Iba1+ cell number, density, or morphology in P10 mice DG C_LI

neuroscience↗

bioRxiv2019

Pax9 is required for cardiovascular development and interacts with Tbx1 in the pharyngeal endoderm to control 4th pharyngeal arch artery morphogenesis.

Developmental defects affecting the heart and aortic arch arteries are a key phenotype observed in DiGeorge syndrome patients and are caused by a microdeletion on chromosome 22q11. Heterozygosity of TBX1, one of the deleted genes, is expressed throughout the pharyngeal arches and is considered a key component for the arch artery defects. Pax9 is expressed in the pharyngeal endoderm and is downregulated in Tbx1 mutant mice. We show here that Pax9 deficient mice are born with complex cardiovascular malformations affecting the outflow tract and aortic arch arteries with failure of the 3rd and 4th pharyngeal arch arteries to form correctly. Transcriptome analysis indicated that Pax9 and Tbx1 may function together, and mice double heterozygous for Tbx1/Pax9 presented with a significantly increased incidence of interrupted aortic arch when compared to Tbx1 heterozygous mice. Using a novel Pax9Cre allele we demonstrated that the site of this Tbx1-Pax9 genetic interaction is in the pharyngeal endoderm, therefore revealing that a Tbx1/Pax9-controlled signalling mechanism emanating from the pharyngeal endoderm is required for critical tissue interactions during normal morphogenesis of the pharyngeal arch artery system.\n\nSummary statementPax9 is required for outflow tract and aortic arch development, and functions together with Tbx1 in the pharyngeal endoderm for 4th arch artery formation.

developmental biology↗