Biology subjects

Satin, J.

Publications and source records attributed to Satin, J..

3 recordsLinked to original sources

bioRxiv2024

Metabolic Adaptations in Adult Spiny Mouse (Acomys) Cardiomyocytes Facilitate Enhanced Cardiac Recovery Following Myocardial Infarction

The adult mammalian heart has limited regenerative capacity following injury, leading to progressive heart failure and mortality. Recent studies have identified the spiny mouse (Acomys) as a unique model for mammalian cardiac regeneration, exhibiting enhanced recovery after myocardial infarction compared to commonly used laboratory mouse strains. However, the cellular and molecular mechanisms underlying this regenerative response remain poorly understood. In this study, we performed a comprehensive characterization of the metabolic adaptations to ischemic injury in cardiomyocytes of Acomys in comparison to the non-regenerative Mus Musculus. To investigate the transcriptomic and metabolomic profiles of cardiomyocytes in response to myocardial infarction, we utilized single-nucleus RNA sequencing (snRNA-seq) in sham-operated animals and 1, 3, and 7 days post-myocardial infarction. Complementary targeted metabolomics, stable isotope-resolved metabolomics, and functional mitochondrial assays were performed on heart tissues from both species to validate the transcriptomic findings and elucidate the metabolic adaptations in cardiomyocytes following ischemic injury. Transcriptomic analysis revealed that Acomys cardiomyocytes upregulate genes associated with glycolysis, the pentose phosphate pathway, and glutathione metabolism while downregulating genes involved in oxidative phosphorylation following injury. These metabolic changes were linked to decreased production of reactive oxygen species and increased antioxidant capacity, evidenced by the upregulation of genes such as Prdx1, Sod1, Sod2, and G6pd. Our targeted metabolomic studies supported these findings, showing a shift from fatty acid oxidation to glycolysis and ancillary biosynthetic pathways in Acomys cardiomyocytes post-injury. Functional mitochondrial studies indicated a higher reliance on glycolysis in Acomys compared to Mus, underscoring the unique metabolic adaptations of Acomys cardiomyocytes. Stable isotope tracing experiments confirmed a shift in glucose utilization from oxidative phosphorylation in Acomys. In conclusion, our study identifies unique metabolic adaptations in Acomys cardiomyocytes that contribute to their enhanced regenerative capacity following myocardial infarction. These findings provide novel insights into the role of metabolism in regulating cardiomyocyte proliferation and cardiac repair in adult mammals. By targeting the specific metabolic pathways and regulators identified in Acomys, such as glycolytic enzymes and PCK2, we may be able to develop innovative therapies to promote cardiac regeneration in patients with ischemic heart disease. Our work highlights the importance of metabolic flexibility in determining cardiomyocyte regenerative responses and establishes Acomys as a valuable model for studying cardiac regeneration in adult mammals. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/595229v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@dba53aorg.highwire.dtl.DTLVardef@3c8a74org.highwire.dtl.DTLVardef@a60251org.highwire.dtl.DTLVardef@e2142c_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2020

Evaluating spiny mice (Acomys) as a model for cardiac research

Complex tissue regeneration is extremely rare among adult mammals. An exception, however, is the superior tissue healing of multiple organs in spiny mice (Acomys). While Acomys species exhibit the remarkable ability to heal complex tissue with minimal scarring, little is known about their cardiac structure and response to cardiac injury. In this study, we first examined baseline Acomys cardiac anatomy and function in comparison with the commonly used laboratory Mus strains (C57BL6 and SWR). Our results demonstrated comparable cardiac anatomy and function between Acomys and Mus, but Acomys exhibited a higher percentage of cardiomyocytes exhibiting immature characteristics. In response to myocardial infarction, all animals experienced a comparable level of initial cardiac damage. However, Acomys demonstrated superior ischemic tolerance and cytoprotection in response to injury as evidenced by cardiac functional stabilization, higher survival rate and smaller scar size 50 days after injury compared to the inbred and outbred mouse strains. Overall, these findings demonstrate augmented myocardial preservation in spiny mice post-MI and establish Acomys as a new adult mammalian model for cardiac research.

developmental biology↗

bioRxiv2020

Heart Slice Culture System Reliably Demonstrates Clinical Drug-Related Cardiotoxicity

The limited availability of human heart tissue and its complex cell composition are major limiting factors for reliable testing drug efficacy, toxicity and understanding mechanism. Recently, we developed a functional human and pig heart slice biomimetic culture system that fully preserves the viability and functionality of 300 {micro}m heart slices for 6 days. Here, we tested the reliability of this culture system in delineating the mechanisms of known anti-cancer drugs that cause cardiomyopathy. We tested three anti-cancer drugs (doxorubicin, trastuzumab, and sunitinib) associated with different mechanisms leading to cardiotoxicity at three concentrations and assessed the effect of these drugs on heart slice viability, structure, function and transcriptome. Slices incubated with any of these drugs for 48 h showed significant loss in viability, cardiomyocyte structure and functionality. Mechanistically, RNA sequencing demonstrated a significant downregulation of cardiac genes and upregulation of oxidative response in doxorubicin-treated tissues. Trastuzumab treatment caused major downregulation in cardiac muscle contraction-related genes, consistent with its clinically known direct effect on cardiomyocytes. Interestingly, sunitinib treatment resulted in significant downregulation of angiogenesis-related genes in line with its mechanism of action. Heart slices are not only able to demonstrate the expected toxicity of doxorubicin and trastuzumab similar to hiPS-derived-cardiomyocytes; they are superior in detecting sunitinib cardiotoxicity phenotypes and mechanism in the clinically relevant concentration range, 100 nM - 1 {micro}M. These results indicate that heart slice tissue culture models have the potential to become a reliable platform for testing drug toxicity and mechanism of action.

cell biology↗