Biology subjects

Samani, A.

Publications and source records attributed to Samani, A..

5 recordsLinked to original sources

bioRxiv2023

DOCK3 regulates normal skeletal muscle regeneration and glucose metabolism

DOCK (dedicator of cytokinesis) is an 11-member family of typical guanine nucleotide exchange factors (GEFs) expressed in the brain, spinal cord, and skeletal muscle. Several DOCK proteins have been implicated in maintaining several myogenic processes such as fusion. We previously identified DOCK3 as being strongly upregulated in Duchenne muscular dystrophy (DMD), specifically in the skeletal muscles of DMD patients and dystrophic mice. Dock3 ubiquitous KO mice on the dystrophin-deficient background exacerbated skeletal muscle and cardiac phenotypes. We generated Dock3 conditional skeletal muscle knockout mice (Dock3 mKO) to characterize the role of DOCK3 protein exclusively in the adult muscle lineage. Dock3 mKO mice presented with significant hyperglycemia and increased fat mass, indicating a metabolic role in the maintenance of skeletal muscle health. Dock3 mKO mice had impaired muscle architecture, reduced locomotor activity, impaired myofiber regeneration, and metabolic dysfunction. We identified a novel DOCK3 interaction with SORBS1 through the C-terminal domain of DOCK3 that may account for its metabolic dysregulation. Together, these findings demonstrate an essential role for DOCK3 in skeletal muscle independent of DOCK3 function in neuronal lineages.

genetics↗

bioRxiv2021

miR-486 is an epigenetic modulator of Duchenne muscular dystrophy pathologies

Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle disorder resulting in muscle weakness and cardiomyopathy. MicroRNAs have been shown to play essential roles in muscle development, metabolism, and disease pathologies. We demonstrated that miR-486 expression is reduced in DMD muscles and its expression levels correlate with dystrophic disease severity. MicroRNA-486 knockout mice developed disrupted myofiber architecture, decreased myofiber size, decreased locomotor activity, increased cardiac fibrosis, and metabolic defects that were exacerbated on the dystrophic mdx5cv background. We integrated RNA-sequencing and chimeric eCLIP-sequencing data to identify direct in vivo targets of miR-486 and associated dysregulated gene signatures in skeletal muscle. In comparison to our DMD mouse muscle transcriptomes, we identified several of these miR-486 muscle targets including known modulators of dystrophinopathy disease symptoms. Together, our studies identify miR-486 as a driver of muscle remodeling in DMD, a useful biomarker for dystrophic disease progression, and highlight chimeric eCLIP-sequencing as a useful tool to identify direct in vivo microRNA target transcripts. O_FIG O_LINKSMALLFIG WIDTH=122 HEIGHT=200 SRC="FIGDIR/small/448387v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@13eeaf5org.highwire.dtl.DTLVardef@1b3b2dborg.highwire.dtl.DTLVardef@a36782org.highwire.dtl.DTLVardef@1e0b95f_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2020

DOCK3 is a dosage-sensitive regulator of skeletal muscle and Duchenne muscular dystrophy-associated pathologies.

DOCK3 is a member of the DOCK family of guanine nucleotide exchange factors that function to regulate cell migration, fusion, and overall viability. Previously, we identified a miR-486/Dock3 signaling cascade that was dysregulated in dystrophin-deficient muscle which resulted in the overexpression of DOCK3, however not much else is known about the role of DOCK3 in muscle. In this work, we characterize the functional role of DOCK3 in normal and dystrophic skeletal muscle. By utilizing Dock3 global knockout (Dock3 KO) mice, we found reducing Dock3 gene via haploinsufficiency in DMD mice improved dystrophic muscle histology, however complete loss of Dock3 worsened overall muscle function on a dystrophin-deficient background. Consistent with this, Dock3 KO mice have impaired muscle architecture and myogenic differentiation defects. Moreover, transcriptomic analyses of Dock3 knockout muscles reveal a decrease in factors known for myogenesis, suggesting a possible mechanism of action. These studies identify DOCK3 as a novel modulator of muscle fusion and muscle health and may yield additional therapeutic targets for treating dystrophic muscle symptoms.

genetics↗

bioRxiv2019

The wasting-associated oncometabolite succinate disrupts myogenesis and impairs skeletal muscle regeneration

BackgroundMuscle wasting is a debilitating co-morbidity affecting most advanced cancer patients. Alongside enhanced muscle catabolism, defects in muscle repair/regeneration contribute to cancer-associated wasting. Among the factors implicated in suppression of muscle regeneration are cytokines that interfere with myogenic signal transduction pathways. Less understood is how other cancer/wasting-associated cues, such as metabolites, contribute to muscle dysfunction. This study investigates how the metabolite succinate affects myogenesis and muscle regeneration. MethodsWe leveraged an established ectopic metabolite treatment (cell permeable dimethyl-succinate) strategy to evaluate the ability of intracellular succinate elevation to 1) affect myoblast homeostasis (proliferation, apoptosis), 2) disrupt protein dynamics and induce wasting-associated atrophy, and 3) modulate in vitro myogenesis. In vivo succinate supplementation experiments (2% succinate, 1% sucrose vehicle) were used to corroborate and extend in vitro observations. Metabolic profiling and functional metabolic studies were then performed to investigate the impact of succinate elevation on mitochondria function. ResultsWe found that in vitro succinate supplementation elevated intracellular succinate about 2-fold, and did not have an impact on proliferation or apoptosis of C2C12 myoblasts. Elevated succinate had minor effects on protein homeostasis ([~]25% decrease in protein synthesis assessed by OPP staining), and no significant effect on myotube atrophy. Succinate elevation interfered with in vitro myoblast differentiation, characterized by significant decreases in late markers of myogenesis and fewer nuclei per myosin heavy chain positive structure (assessed by immunofluorescence staining). While mice orally administered succinate did not exhibit changes in overall body composition or whole muscle weights, these mice displayed smaller muscle myofiber diameters ([~]6% decrease in the mean of non-linear regression curves fit to the histograms of minimum feret diameter distribution), which was exacerbated when muscle regeneration was induced with barium chloride injury. Significant decreases in the mean of non-linear regression curves fit to the histograms of minimum feret diameter distributions were observed 7 days and 28 days post injury. Elevated numbers of myogenin positive cells (3-fold increase) supportive of the differentiation defects observed in vitro were observed 28 days post injury. Metabolic profiling and functional metabolic assessment of myoblasts revealed that succinate elevation caused both widespread metabolic changes and significantly lowered maximal cellular respiration ([~]35% decrease). ConclusionsThis study broadens the repertoire of wasting-associated factors that can directly modulate muscle progenitor cell function and strengthens the hypothesis that metabolic derangements are significant contributors to impaired muscle regeneration, an important aspect of cancer-associated muscle wasting.

cancer biology↗

bioRxiv2019

An Oculometrics-based Biofeedback System to Impede Fatigue Development during Computer Work: a Proof-of-Concept Study

A biofeedback system may objectively identify fatigue and provide an individualized timing plan for micro-breaks. We developed and implemented a biofeedback system based on oculometrics using continuous recordings of eye movements and pupil dilations to moderate fatigue development in its early stages. Twenty healthy young participants (10 males and females) performed a cyclic computer task for 31-35 min over two sessions: 1) self-triggered micro-breaks (manual sessions), and 2) biofeedback-triggered micro-breaks (automatic sessions). The sessions were held with one-week inter-session interval and in a counterbalanced order across participants. Each session involved 180 cycles of the computer task and after each 20 cycles (a segment), the task paused for 5-s to acquire perceived fatigue using Karolinska Sleepiness Scale (KSS). Following the pause, a 25-s micro-break involving seated exercises was carried out whether it was triggered by the biofeedback system if the fatigue state (KSS[≥]5) was detected in automatic sessions or by the participants in manual sessions. National Aeronautics and Space Administration Task Load Index (NASA-TLX) was administered after sessions. The functioning core of the biofeedback system was based on a Decision Tree Ensemble model for fatigue classification, which was developed using an oculometrics dataset previously collected during the same computer task. The biofeedback system identified fatigue states with a mean accuracy of approx. 70% and remained robust against circadian rhythms. Perceived workload obtained from NASA-TLX was significantly lower in the automatic sessions compared with the manual sessions, p=0.01 Cohens d=0.89. The results give support to the robustness and effectiveness of integrating oculometrics-based biofeedback in time planning of micro-breaks to impede fatigue development during computer work.

physiology↗