Biology subjects

Sanchis, D.

Publications and source records attributed to Sanchis, D..

3 recordsLinked to original sources

bioRxiv2020

Trans control of cardiac mRNA translation in a protein length-dependent fashion

Little is known about the impact of naturally occurring genetic variation on the rates with which proteins are synthesized by ribosomes. Here, we investigate how genetic influences on mRNA translational efficiency are associated with complex disease phenotypes using a panel of rat recombinant inbred lines. We identify a locus for cardiac hypertrophy that is associated with a translatome-wide and protein length-dependent shift in translational efficiency. This master regulator primarily affects the translation of very short and very long protein-coding sequences, altering the physiological stoichiometric translation rates of sarcomere proteins. Mechanistic dissection of this locus points to altered ribosome assembly, characterized by accumulation of polysome half-mers, changed ribosomal configurations and misregulation of the small nucleolar RNA SNORA48. We postulate that this locus enhances a pre-existing negative correlation between protein length and translation initiation in diseased hearts. Our work shows that a single genomic locus can trigger a complex, translation-driven molecular mechanism that contributes to phenotypic variability between individuals. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/133298v1_ufig1.gif" ALT="Figure 1"> View larger version (62K): org.highwire.dtl.DTLVardef@e46986org.highwire.dtl.DTLVardef@1cc0b08org.highwire.dtl.DTLVardef@e86011org.highwire.dtl.DTLVardef@1fb3706_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIGenetic variability impacts protein synthesis rates in a rat model for cardiac hypertrophy C_LIO_LIA trans locus affects stoichiometric translation rates of cardiac sarcomeric proteins C_LIO_LIThis master regulator locus induces a global, protein length-dependent shift in translation C_LIO_LIDysregulated ribosome assembly induces half-mer formation and affects translation initiation rate C_LI

genetics↗

bioRxiv2019

AKT2 deficiency causes sarcopenia and metabolic disorder of skeletal muscle

Skeletal muscle is responsible for the majority of glucose disposal in the body. Insulin resistance in the skeletal muscle accounts for 85-90% of the impairment of total body glucose disposal in patients with tye 2 diabetes (T2D). However, the mechanism remains controversial. AKT2 is a protein kinase performing important functions in the regulation of glucose metabolism. We observed that mice deficient for AKT2 (AKT2 KO) exhibited decreased body weight and lean mass and showed impaired glucose tolerance, compared to their age- and gender-matched wild type mice (WT). Therefore, to test whether AKT2 deficiency causes deficits in skeletal muscle development and metabolism, we analyzed the expression of molecules related to skeletal muscle development, glucose uptake and metabolism in young (3 months) and old (8 months) mice. We found that AMPK phosphorylation and MEF2A expression were downregulated in young AKT2 KO mice, and this downregulation was inverted by AMPK activation. We also observed reduced mtDNA abundance and reduced expression of genes involved in mitochondrial biogenesis in the skeletal muscle of adult AKT2 KO mice, which was prevented by AMPK activation. However, GLUT4 expression was regulated by AKT2 in an AMPK-independent manner in skeletal muscle. During high-fat-diet (HFD)-induced obesity, AKT2 KO mice exhibited increased insulin resistance compared to WT mice. Our study establishes a new and important function of AKT2 in regulating glucose uptake and AMPK-dependent development and mitochondrial biogenesis in skeletal muscle.

molecular biology↗

bioRxiv2018

Genome Wide Meta-Analysis identifies new loci associated with cardiac phenotypes and uncovers a common genetic signature shared by heart function and Alzheimer’s disease

AimsEchocardiography has become an indispensable tool for the study of heart performance, improving the monitoring of individuals with cardiac diseases. Diverse genetic factors associated with echocardiographic measures of heart structure and functions have been previously reported. The impact of several apoptotic genes in heart development identified in experimental models prompted us to assess their potential association with indicators of human cardiac function. This study started with the aim to investigate the possible association of variants of apoptotic genes with echocardiographic traits and to identify new genetic markers associated with cardiac function.\n\nMethods and resultsGenome wide data from different studies were obtained from public repositories. After quality control and imputation, association analyses confirm the role of caspases and other apoptosis related genes with cardiac phenotypes. Moreover, enrichment analysis showed an over-representation of genes, including some apoptotic regulators, associated with Alzheimers disease (AD). We further explored this unexpected observation which was confirmed by genetic correlation analyses.\n\nConclusionsOur findings show the association of apoptotic gene variants with echocardiographic indicators of heart function and reveal a novel potential genetic link between echocardiographic measures in healthy populations and cognitive decline later on in life. These findings may have important implications for preventative strategies combating Alzheimers disease.

genetics↗