Biology subjects

Mansur, A.

Publications and source records attributed to Mansur, A..

6 recordsLinked to original sources

bioRxiv2025

KLHL41 orchestrates sarcomere assembly and size to drive skeletal muscle hypertrophy in vivo

Sarcomere assembly and growth are fundamental processes essential for the development, function, and repair of skeletal muscle. However, the mechanisms underlying sarcomere formation and assembly in vivo, which are critical for the formation of functional myofibers in vertebrates, remain poorly understood. Defects in sarcomeres contribute to muscle dysfunction in numerous genetic and acquired myopathies, yet the lack of a clear understanding of specific sarcomeric defects has hindered the development of effective therapies. Nemaline myopathy (NM) is caused by mutations in genes that primarily affect sarcomere structure and function. The disease is clinically heterogeneous, with the congenital form being the most severe. Using zebrafish models of congenital forms of NM, we investigated sarcomere assembly in vivo during skeletal muscle development to identify key steps contributing to myofibril formation and muscle growth under both normal and disease conditions. Our findings demonstrate that the gene encoding the sarcomeric protein KLHL41 plays a critical role in the formation and directional organization of new sarcomeres within developing myofibrils, facilitating both radial and longitudinal muscle growth. Dysregulation of sarcomeric proteins and impaired protein turnover in the KLHL41-NM zebrafish model resulted in the development of sarcomeric defects. Moreover, we show that the interaction between the KLHL41-troponin complex is essential for muscle growth and cross-bridge regulation in developing muscle. These studies address a significant gap in the understanding of sarcomeric defects in myopathies and will help guide the development of targeted therapies aimed at rescuing these processes.

genetics↗

bioRxiv2024

The relationship between brain activation and mitochondrial complex I protein levels during cognitive function in healthy humans: an BCPP-EF PET and functional MRI study of task switching

Mitochondrial complex I is the largest enzyme complex in the respiratory chain and can be non-invasively measured using [18F]BCPP-EF positron emission tomography (PET). Neurological conditions associated with mitochondria complex I pathology are also associated with altered blood oxygen level dependent (BOLD) response and impairments in cognition. To evaluate the link between mitochondrial complex I, cognition and associated neural activity, 23 cognitively healthy adults underwent a [18F]BCPP-EF PET scan and a functional magnetic resonance imaging (fMRI) scan during which they performed a task switching exercise. We found significant positive associations between [18F]BCPP-EF volume of distribution (VT), which measures mitochondrial complex I levels and the task switching fMRI response (Partial Least Squares (PLS) Canonical Analysis (CA), first component r=0.51, p=0.03). Exploratory Pearsons correlations showed significant positive associations between mitochondrial complex I levels and the fMRI response in regions including the dorsolateral prefrontal cortex (r=0.61, p=0.0019), insula (r=0.46, p=0.0264) parietal-precuneus (r=0.51, p=0.0139) and anterior cingulate cortex (r=0.45, p=0.0293). Mitochondrial complex I levels across task-relevant regions were also predictive of task switching accuracy (PLS-Regression (PLS-R), R2=0.48, RMSE=0.154, p=0.011) and of switch cost (PLS-R, R^2=0.38, RMSE=0.07, p=0.048). Our findings suggest that higher mitochondrial complex I levels may underlie an individuals ability to exhibit a stronger BOLD response during task switching and are predictive of better task switching performance. This provides the first evidence linking the BOLD response with mitochondrial complex I and suggests a possible biological mechanism for aberrant BOLD response in conditions associated with mitochondrial complex I dysfunction, that should be tested in future studies.

neuroscience↗

bioRxiv2024

Spontaneous brain activity and synaptic density in schizophrenia: a combined UCB-J PET and fMRI study

Schizophrenia is associated with altered Amplitude of Low Frequency Fluctuations (ALFF), a functional Magnetic Resonance Imaging (fMRI) measure of spontaneous brain activity at rest. ALFF in healthy controls has been linked with presynaptic density levels measured by [11C]UCB-J positron emission tomography (PET). Given the growing body of evidence for low presynaptic density levels in schizophrenia, we set out to test if altered [11C]UCB-J binding may be associated with changes in ALFF in schizophrenia, and secondly to test whether the relationships between ALFF and [11C]UCB-J binding differ at the group level. Subjects with schizophrenia had higher ALFF in the medial prefrontal cortex and other regions, in line with published meta-analyses. In control subjects, there was a significant positive relationship between [11C]UCB-J distribution volume ratio (DVRcs) and ALFF in the medial prefrontal cortex (r=0.54, p=0.0365, n=16), but not in subjects with schizophrenia (r=-0.14, p=0.5564, n=22); r-coefficients significantly differed between groups (Zobserved=2.07, p=0.019). At the whole brain level, there were significant positive correlations between [11C]UCB-J DVRcs and ALFF in control subjects in the putamen, insular cortex, precentral gyrus and occipital regions, while in the schizophrenia group, there were significant positive correlations in the bilateral dorsolateral prefrontal cortex and negative correlations in the cuneus, parietal lobule and supramarginal gurus. Correlation coefficients were significantly different between groups across all cortical and subcortical regions with both higher and lower correlation coefficients in the control group. Our results suggest a link between spontaneous brain activity and presynaptic density in control subjects and that this relationship may be disrupted in schizophrenia patients, despite higher ALFF in this group, indicating altered neurobiological mechanisms. Widespread significant differences in ALFF-[11C]UCB-J DVRcs correlation coefficients between controls and schizophrenia subjects highlight the complexity of synaptic dysfunction in schizophrenia and underscore the need for further research to explore the underlying biological mechanisms.

neuroscience↗

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↗