Biology subjects

Mansur, A.

Publications and source records attributed to Mansur, A..

3 recordsLinked to original sources

bioRxiv2022

Glycerolipid defects in skeletal muscle contribute to rhabdomyolysis in Tango2 deficiency

Rhabdomyolysis is a clinical emergency characterized by severe muscle damage resulting in the release of intracellular muscle components leading to myoglobinuria and in severe cases, acute kidney failure. Rhabdomyolysis is caused by genetic factors that are linked to increased disease susceptibility in response to extrinsic triggers. Recessive mutations in TANGO2 result in episodic rhabdomyolysis, metabolic crises, encephalopathy and cardiac arrhythmia, the underlying mechanism contributing to disease onset in response to specific triggers remains unclear. To address these challenges, we created a zebrafish model of Tango2 deficiency. Here we show that loss of Tango2 in zebrafish results in growth defects, early lethality and increased susceptibility of muscle defects similar to TANGO2 patients. Detailed analyses of skeletal muscle revealed defects in the sarcoplasmic reticulum and mitochondria at the onset of disease development. The sarcoplasmic reticulum (SR) constitutes the primary lipid biosynthesis site and regulates calcium handling in skeletal muscle to control excitation-contraction coupling. Tango2 deficient SR exhibits increased sensitivity to calcium release that was partly restored by inhibition of Ryr1-mediated Ca2+ release in skeletal muscle. Using lipidomics, we identified alterations in the glycerolipid state of tango2 mutants which is critical for membrane stability and energy balance. Therefore, these studies provide insight into key disease processes in Tango2 deficiency and increased our understanding of how specific defects can predispose to environmental triggers in TANGO2-related disorders.

genetics↗

bioRxiv2022

Dynamic regulation of inter-organelle communication by ubiquitylation controls skeletal muscle development and disease onset

Ubiquitin-proteasome system (UPS) dysfunction is associated with the pathology of a wide range of human diseases including myopathies and muscular atrophy. However, the mechanistic understanding of specific components on the regulation of protein turnover during development and disease progression in skeletal muscle is unclear. Mutations in KLHL40, an E3 ubiquitin ligase cullin3 (CUL3) substrate-specific adapter protein result in a severe form of congenital nemaline myopathy, but the events that initiate the pathology and the mechanism through which it becomes pervasive, remains poorly understood. To characterize the KLHL40-regulated ubiquitin modified proteome during skeletal muscle development and disease onset, we used global, quantitative mass spectrometry-based ubiquitylome and global proteome analyses of klhl40 mutant zebrafish during disease progression. Global proteomics during skeletal muscle development revealed extensive remodeling of functional modules linked with sarcomere formation, energy and biosynthetic metabolic processes and vesicle trafficking. Combined analysis of klh40 mutant muscle proteome and ubiquitylome identified thin filament proteins, metabolic enzymes and ER-Golgi vesicle trafficking pathway proteins regulated by ubiquitylation during muscle development. Our studies identified a role for KLHL40 as a negative regulator of ER-Golgi anterograde trafficking through ubiquitin-mediated protein degradation of secretion associated Ras related GTPase1a (Sar1a). In KLHL40 deficient muscle, defects in ER exit site vesicle formation alter Golgi compartment and downstream transport of extracellular cargo proteins, resulting in structural and functional abnormalities. Our work reveals that the muscle proteome is dynamically fine-tuned by ubiquitylation to regulate skeletal muscle development and uncovers new disease mechanisms for therapeutic development in patients. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/501000v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1950696org.highwire.dtl.DTLVardef@e37313org.highwire.dtl.DTLVardef@9804a6org.highwire.dtl.DTLVardef@59527f_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2021

Tension-driven multi-scale self-organisation in human iPSC-derived muscle fibers

Human muscle is a hierarchically organised tissue with its contractile cells called myofibers packed into large myofiber bundles. Each myofiber contains periodic myofibrils built by hundreds of contractile sarcomeres that generate large mechanical forces. To better understand the mechanisms that coordinate human muscle morphogenesis from tissue to molecular scales, we adopted a simple in vitro system using induced pluripotent stem cell-derived human myogenic precursors. When grown on an unrestricted two-dimensional substrate, developing myofibers spontaneously align and self-organise into higher-order myofiber bundles, which grow and consolidate to stable sizes. Following a transcriptional boost of sarcomeric components, myofibrils assemble into chains of periodic sarcomeres that emerge across the entire myofiber. By directly probing tension we found that tension build-up precedes sarcomere assembly and increases within each assembling myofibril. Furthermore, we found that myofiber ends stably attach to other myofibers using integrin-based attachments and thus myofiber bundling coincides with stable myofiber bundle attachment in vitro. A failure in stable myofiber attachment results in a collapse of the myofibrils. Overall, our results strongly suggest that mechanical tension across sarcomeric components as well as between differentiating myofibers is key to coordinate the multi-scale self-organisation of muscle morphogenesis.

developmental biology↗