scholarly journals Disease Affects Bdnf Expression in Synaptic and Extrasynaptic Regions of Skeletal Muscle of Three SBMA Mouse Models

2019 ◽  
Vol 20 (6) ◽  
pp. 1314 ◽  
Author(s):  
Katherine Halievski ◽  
Samir Nath ◽  
Masahisa Katsuno ◽  
Hiroaki Adachi ◽  
Gen Sobue ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Mouse Models ◽  
Contractile Function ◽  
Muscular Atrophy ◽  
Synaptic Function ◽  
Bdnf Expression ◽  
Gene Dysregulation ◽  
Synaptic Region ◽  
Spinal Bulbar Muscular Atrophy

Spinal bulbar muscular atrophy (SBMA) is a slowly progressive, androgen-dependent neuromuscular disease in men that is characterized by both muscle and synaptic dysfunction. Because gene expression in muscle is heterogeneous, with synaptic myonuclei expressing genes that regulate synaptic function and extrasynaptic myonuclei expressing genes to regulate contractile function, we used quantitative PCR to compare gene expression in these two domains of muscle from three different mouse models of SBMA: the “97Q” model that ubiquitously expresses mutant human androgen receptor (AR), the 113Q knock-in (KI) model that expresses humanized mouse AR with an expanded glutamine tract, and the “myogenic” model that overexpresses wild-type rat AR only in skeletal muscle. We were particularly interested in neurotrophic factors because of their role in maintaining neuromuscular function via effects on both muscle and synaptic function, and their implicated role in SBMA. We confirmed previous reports of the enriched expression of select genes (e.g., the acetylcholine receptor) in the synaptic region of muscle, and are the first to report the synaptic enrichment of others (e.g., glial cell line-derived neurotrophic factor). Interestingly, all three models displayed comparably dysregulated expression of most genes examined in both the synaptic and extrasynaptic domains of muscle, with only modest differences between regions and models. These findings of comprehensive gene dysregulation in muscle support the emerging view that skeletal muscle may be a prime therapeutic target for restoring function of both muscles and motoneurons in SBMA.

scholarly journals Microarray Analysis of Gene Expression by Skeletal Muscle of Three Mouse Models of Kennedy Disease/Spinal Bulbar Muscular Atrophy

PLoS ONE ◽  
2010 ◽  
Vol 5 (9) ◽  
pp. e12922 ◽  
Author(s):  
Kaiguo Mo ◽  
Zak Razak ◽  
Pengcheng Rao ◽  
Zhigang Yu ◽  
Hiroaki Adachi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Mouse Models ◽  
Microarray Analysis ◽  
Muscular Atrophy ◽  
Spinal Bulbar Muscular Atrophy

scholarly journals Gene expression changes controlling distinct adaptations in the heart and skeletal muscle of a hibernating mammal

2015 ◽  
Vol 47 (3) ◽  
pp. 58-74 ◽  
Author(s):  
Katie L. Vermillion ◽  
Kyle J. Anderson ◽  
Marshall Hampton ◽  
Matthew T. Andrews
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Cardiac Tissue ◽  
Contractile Function ◽  
Oxygen Demand ◽  
Oxidative Capacity ◽  
Disuse Atrophy ◽  
Functional Requirements ◽  
Skeletal Muscle Function ◽  
Illumina Hiseq

Throughout the hibernation season, the thirteen-lined ground squirrel ( Ictidomys tridecemlineatus) experiences extreme fluctuations in heart rate, metabolism, oxygen consumption, and body temperature, along with prolonged fasting and immobility. These conditions necessitate different functional requirements for the heart, which maintains contractile function throughout hibernation, and the skeletal muscle, which remains largely inactive. The adaptations used to maintain these contractile organs under such variable conditions serves as a natural model to study a variety of medically relevant conditions including heart failure and disuse atrophy. To better understand how two different muscle tissues maintain function throughout the extreme fluctuations of hibernation we performed Illumina HiSeq 2000 sequencing of cDNAs to compare the transcriptome of heart and skeletal muscle across the circannual cycle. This analysis resulted in the identification of 1,076 and 1,466 differentially expressed genes in heart and skeletal muscle, respectively. In both heart and skeletal muscle we identified a distinct cold-tolerant mechanism utilizing peroxisomal metabolism to make use of elevated levels of unsaturated depot fats. The skeletal muscle transcriptome also shows an early increase in oxidative capacity necessary for the altered fuel utilization and increased oxygen demand of shivering. Expression of the fetal gene expression profile is used to maintain cardiac tissue, either through increasing myocyte size or proliferation of resident cardiomyocytes, while skeletal muscle function and mass are protected through transcriptional regulation of pathways involved in protein turnover. This study provides insight into how two functionally distinct muscles maintain function under the extreme conditions of mammalian hibernation.

scholarly journals 34. Phi C31 Integrase System Enhances Dystrophin Gene Expression in Skeletal Muscle of Mouse Models for Duchenne Muscular Dystrophy

2006 ◽  
Vol 13 ◽  
pp. S14-S15
Author(s):  
Carmen Bertoni ◽  
Sohail Jarrahian ◽  
Thurman M. Wheeler ◽  
Yining Li ◽  
Eric C. Olivares ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Mouse Models ◽  
Dystrophin Gene

scholarly journals Dysregulation of the Tweak/Fn14 pathway in skeletal muscle of spinal muscular atrophy mice

2021 ◽  
Author(s):  
Katharina E Meijboom ◽  
Emily McFall ◽  
Daniel Anthony ◽  
Benjamin Edwards ◽  
Sabrina Kubinski ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Spinal Muscular Atrophy ◽  
Mouse Models ◽  
Muscle Atrophy ◽  
Muscular Atrophy ◽  
Critical Role ◽  
Pharmacological Intervention ◽  
Muscle Pathology ◽  
Developing Muscle

Spinal muscular atrophy (SMA) is a childhood neuromuscular disorder caused by depletion of the survival motor neuron (SMN) protein. SMA is characterized by the selective death of spinal cord motor neurons, leading to progressive muscle wasting. Loss of skeletal muscle in SMA is a combination of denervation-induced muscle atrophy and intrinsic muscle pathologies. Elucidation of the pathways involved is essential to identify the key molecules that contribute to and sustain muscle pathology. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/TNF receptor superfamily member fibroblast growth factor inducible 14 (Fn14) pathway has been shown to play a critical role in the regulation of denervation-induced muscle atrophy as well as muscle proliferation, differentiation and metabolism in adults. However, it is not clear whether this pathway would be important in highly dynamic and developing muscle. We thus investigated the potential role of the TWEAK/Fn14 pathway in SMA muscle pathology, using the severe Taiwanese Smn-/-;SMN2 and the less severe Smn2B/- SMA mice, which undergo a progressive neuromuscular decline in the first three post-natal weeks. Here, we report significantly dysregulated expression of the TWEAK/Fn14 pathway during disease progression in skeletal muscle of the two SMA mouse models. In addition, siRNA-mediated Smn knockdown in C2C12 myoblasts suggests a genetic interaction between Smn and the TWEAK/Fn14 pathway. Further analyses of SMA, Tweak-/- and Fn14-/- mice revealed dysregulated myopathy, myogenesis and glucose metabolism pathways as a common skeletal muscle feature, and providing further evidence in support of a relationship between the TWEAK/Fn14 pathway and Smn. Finally, a pharmacological intervention (Fc-TWEAK) to upregulate the activity of the TWEAK/Fn14 pathway improved disease phenotypes in the two SMA mouse models. Our study provides novel mechanistic insights into the molecular players that contribute to muscle pathology in SMA and into the role of the TWEAK/Fn14 pathway in developing muscle.

scholarly journals Neuromuscular junctions are pathological but not denervated in two mouse models of spinal bulbar muscular atrophy

2016 ◽  
Vol 25 (17) ◽  
pp. 3768-3783 ◽  
Author(s):  
Jessica E. Poort ◽  
Mary B. Rheuben ◽  
S. Marc Breedlove ◽  
Cynthia L. Jordan
Keyword(s):  
Mouse Models ◽  
Neuromuscular Junctions ◽  
Muscular Atrophy ◽  
Spinal Bulbar Muscular Atrophy

scholarly journals Antiandrogen Flutamide Protects Male Mice From Androgen-Dependent Toxicity in Three Models of Spinal Bulbar Muscular Atrophy

Endocrinology ◽  
2014 ◽  
Vol 155 (7) ◽  
pp. 2624-2634 ◽  
Author(s):  
Kayla J. Renier ◽  
Sandra M. Troxell-Smith ◽  
Jamie A. Johansen ◽  
Masahisa Katsuno ◽  
Hiroaki Adachi ◽  
...  
Keyword(s):  
Mouse Models ◽  
Therapeutic Potential ◽  
Late Onset ◽  
Muscular Atrophy ◽  
Motor Dysfunction ◽  
Male Mice ◽  
Therapeutic Value ◽  
Spinal Bulbar Muscular Atrophy ◽  
Proof Of Principle ◽  
Polyq Expansion

Spinal and bulbar muscular atrophy (SBMA) is a late-onset, progressive neurodegenerative disease linked to a polyglutamine (polyQ) expansion in the androgen receptor (AR). Men affected by SBMA show marked muscle weakness and atrophy, typically emerging midlife. Given the androgen-dependent nature of this disease, one might expect AR antagonists to have therapeutic value for treating SBMA. However, current work from animal models suggests otherwise, raising questions about whether polyQ-expanded AR exerts androgen-dependent toxicity through mechanisms distinct from normal AR function. In this study, we asked whether the nonsteroidal AR antagonist flutamide, delivered via a time-release pellet, could reverse or prevent androgen-dependent AR toxicity in three different mouse models of SBMA: the AR97Q transgenic (Tg) model, a knock-in (KI) model, and a myogenic Tg model. We find that flutamide protects mice from androgen-dependent AR toxicity in all three SBMA models, preventing or reversing motor dysfunction in the Tg models and significantly extending the life span in KI males. Given that flutamide effectively protects against androgen-dependent disease in three different mouse models of SBMA, our data are proof of principle that AR antagonists have therapeutic potential for treating SBMA in humans and support the notion that toxicity caused by polyQ-expanded AR uses at least some of the same mechanisms as normal AR before diverging to produce disease and muscle atrophy.

scholarly journals Mechanisms of skeletal muscle injury and repair revealed by gene expression studies in mouse models

2007 ◽  
Vol 582 (2) ◽  
pp. 825-841 ◽  
Author(s):  
Gordon L. Warren ◽  
Mukesh Summan ◽  
Xin Gao ◽  
Rebecca Chapman ◽  
Tracy Hulderman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Mouse Models ◽  
Muscle Injury ◽  
Skeletal Muscle Injury ◽  
Expression Studies ◽  
Gene Expression Studies ◽  
Injury And Repair

scholarly journals Transcriptional profiling reveals extraordinary diversity among skeletal muscle tissues

2017 ◽  
Author(s):  
Erin E Terry ◽  
Xiping Zhang ◽  
Christy Hoffmann ◽  
Laura D Hughes ◽  
Scott A Lewis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Mrna Expression ◽  
Skeletal Muscles ◽  
Contractile Function ◽  
Expression Profiles ◽  
Differentially Expressed ◽  
Data Set ◽  
Transcriptional Profiles ◽  
Muscle Tissues

AbstractSkeletal muscle comprises a family of diverse tissues with highly specialized morphology, function, and metabolism. Many acquired diseases – including HIV, COPD, cancer cachexia, critical illness myopathy, and sepsis – affect specific muscles while sparing others. Even monogenic muscular dystrophies tend to selectively affect certain muscle groups, despite their causative genetic mutations being present in all tissues. These observations suggest that factors intrinsic to muscle tissues influence their susceptibility to various disease mechanisms. Nevertheless, most studies have not addressed transcriptional diversity among skeletal muscles. Here we use RNA sequencing (RNA-seq) to profile global mRNA expression in a wide array of skeletal, smooth, and cardiac muscle tissues from mice and rats. Our data set, MuscleDB, reveals extensive transcriptional diversity, with greater than 50% of transcripts differentially expressed among skeletal muscle tissues. This diversity is only partly explained by fiber type composition and developmental history, suggesting that specialized transcriptional profiles establish the functional identity of muscle tissues. We find conservation in the transcriptional profiles across species as well as between males and females, indicating that these data may be useful in predicting gene expression in related species. Notably, thousands of differentially expressed genes in skeletal muscle are associated with human disease, and hundreds of these genes encode targets of drugs on the market today. We detect mRNA expression of hundreds of putative myokines that may underlie the endocrine functions of skeletal muscle. In addition to demonstrating the intrinsic diversity of skeletal muscles, these data provide a resource for generating testable hypotheses regarding the mechanisms that establish differential disease susceptibility in muscle.Significance StatementSkeletal muscles are a diverse family of tissues with a common contractile function but divergent morphology, development, and metabolism. One need only reflect on the different functions of limb muscles and the diaphragm to realize the highly specialized nature of these tissues. Nevertheless, every study of global gene expression has analyzed at most one representative skeletal muscle. Here we measure gene expression from 11 different skeletal muscles in mice and rats. We show that there is no such thing as a representative skeletal muscle, as gene expression profiles vary widely among the tissues analyzed. These data are an important resource for pharmacologists, tissue engineers, and investigators studying the mechanisms of cellular specialization.

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