Transcriptional regulation and alternative splicing cooperate in muscle fiber-type specification in flies and mammals

Spletter, Maria L.; Schnorrer, Frank

doi:10.1016/j.yexcr.2013.10.007

Cited by 53 publications

(46 citation statements)

References 77 publications

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“…We examined TDP-43 because TDP-43 aggregates have been reported in inclusion body myositis, where ubiquitin aggregates are also found. 20 , 30 , 35 , 36 In addition, TDP-43 functions in alternative mRNA splicing 37 , 38 ; and proper splicing is required for normal skeletal muscle function, 39 may regulate DUX4-fl mRNA production, 2 and may be aberrant in myopathies including FSHD. 40 …”

Section: Resultsmentioning

confidence: 99%

Expression of FSHD‐related DUX4‐FL alters proteostasis and induces TDP‐43 aggregation

Homma

Beermann

Boyce

et al. 2015

Ann Clin Transl Neurol

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ObjectivePathogenesis in facioscapulohumeral muscular dystrophy (FSHD) appears to be due to aberrant expression, particularly in skeletal muscle nuclei, of the full-length isoform of DUX4 (DUX4-FL). Expression of DUX4-FL is known to alter gene expression and to be cytotoxic, but cell responses to DUX4-FL are not fully understood. Our study was designed to identify cellular mechanisms of pathogenesis caused by DUX4-FL expression.MethodsWe used human myogenic cell cultures to analyze the effects of DUX4-FL when it was expressed either from its endogenous promoter in FSHD cells or by exogenous expression using BacMam vectors. We focused on determining the effects of DUX4-FL on protein ubiquitination and turnover and on aggregation of TDP-43.ResultsHuman FSHD myotubes with endogenous DUX4-FL expression showed both altered nuclear and cytoplasmic distributions of ubiquitinated proteins and aggregation of TDP-43 in DUX4-FL-expressing nuclei. Similar changes were found upon exogenous expression of DUX4-FL, but were not seen upon expression of the non-toxic short isoform DUX4-S. DUX4-FL expression also inhibited protein turnover in a model system and increased the amounts of insoluble ubiquitinated proteins and insoluble TDP-43. Finally, inhibition of the ubiquitin–proteasome system with MG132 produced TDP-43 aggregation similar to DUX4-FL expression.InterpretationsOur results identify DUX4-FL-induced inhibition of protein turnover and aggregation of TDP-43, which are pathological changes also found in diseases such as amyotrophic lateral sclerosis and inclusion body myopathy, as potential pathological mechanisms in FSHD.

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Section: Resultsmentioning

confidence: 99%

Expression of FSHD‐related DUX4‐FL alters proteostasis and induces TDP‐43 aggregation

Homma

Beermann

Boyce

et al. 2015

Ann Clin Transl Neurol

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“…IFMs are fast-twitching muscles with high mitochondrial content necessary for long-lasting oxidative metabolism. In addition to calcium stimulation, these asynchronous muscles require stretch activation to induce their contractions [75]. In young animals, no significant increase in muscle degeneration was observed in animals bearing only one copy of Dg, yki or kbr (Dg O55 /+, yki B5 /+, or kbr del /+, respectively) or in flies trans-heterozygous for Dg and Hippo pathway components (Dg O55 /yki B5 or Dg O55 /+; kbr del /+), when compared to controls (w 1118 /+, 7 days old, Fig.…”

Section: Dg Binds Extracellular Laminina and Cytoskeletal Proteins Inmentioning

confidence: 99%

Profiling of the muscle-specific dystroglycan interactome reveals the role of Hippo signaling in muscular dystrophy and age-dependent muscle atrophy

Yatsenko

Kucherenko

Xie

et al. 2020

BMC Med

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Background: Dystroglycanopathies are a group of inherited disorders characterized by vast clinical and genetic heterogeneity and caused by abnormal functioning of the ECM receptor dystroglycan (Dg). Remarkably, among many cases of diagnosed dystroglycanopathies, only a small fraction can be linked directly to mutations in Dg or its regulatory enzymes, implying the involvement of other, not-yet-characterized, Dg-regulating factors. To advance disease diagnostics and develop new treatment strategies, new approaches to find dystroglycanopathy-related factors should be considered. The Dg complex is highly evolutionarily conserved; therefore, model genetic organisms provide excellent systems to address this challenge. In particular, Drosophila is amenable to experiments not feasible in any other system, allowing original insights about the functional interactors of the Dg complex. Methods: To identify new players contributing to dystroglycanopathies, we used Drosophila as a genetic muscular dystrophy model. Using mass spectrometry, we searched for muscle-specific Dg interactors. Next, in silico analyses allowed us to determine their association with diseases and pathological conditions in humans. Using immunohistochemical, biochemical, and genetic interaction approaches followed by the detailed analysis of the muscle tissue architecture, we verified Dg interaction with some of the discovered factors. Analyses of mouse muscles and myocytes were used to test if interactions are conserved in vertebrates. Results: The muscle-specific Dg complexome revealed novel components that influence the efficiency of Dg function in the muscles. We identified the closest human homologs for Dg-interacting partners, determined their significant enrichment in disease-associations, and verified some of the newly identified Dg interactions. We found that Dg associates with two components of the mechanosignaling Hippo pathway: the WW domain-containing proteins Kibra and Yorkie. Importantly, this conserved interaction manages adult muscle size and integrity.

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“…Hence, the ATP demand of these muscle fibers during flight is extremely high. With its strict aerobic metabolism and its stretch activation mechanism requiring high mechanical tension, insect flight muscles biomechanically and energetically resemble the mammalian heart muscle 14,15 .…”

Section: To Investigate the Interplay Between Myofibrils And Mitochonmentioning

confidence: 99%

Myofibril and mitochondria morphogenesis are coordinated by a mechanical feedback mechanism in muscle

Avellaneda

Rodier

Daian

et al. 2020

Preprint

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Complex animals build specialised muscle to match specific biomechanical and energetic needs. Hence, composition and architecture of sarcomeres as well as mitochondria are muscle type specific. However, mechanisms coordinating mitochondria with sarcomere morphogenesis are elusive. Here we use Drosophila muscles to demonstrate that myofibril and mitochondria morphogenesis are intimately linked. In flight muscles, the muscle selector spalt instructs mitochondria to intercalate between myofibrils, which in turn mechanically constrain mitochondria into elongated shapes. Conversely in cross-striated muscles, mitochondria networks surround myofibril bundles, contacting myofibrils only with thin extensions. To investigate the mechanism causing these differences, we manipulated mitochondrial dynamics and found that increased mitochondrial fusion during myofibril assembly prevents mitochondrial intercalation in flight muscles. Strikingly, this coincides with the expression of cross-striated muscle specific sarcomeric proteins. Consequently, flight muscle myofibrils convert towards a partially cross-striated architecture. Together, these data suggest a biomechanical feedback mechanism downstream of spalt synchronizing mitochondria with myofibril morphogenesis.

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Transcriptional regulation and alternative splicing cooperate in muscle fiber-type specification in flies and mammals

Cited by 53 publications

References 77 publications

Expression of FSHD‐related DUX4‐FL alters proteostasis and induces TDP‐43 aggregation

Expression of FSHD‐related DUX4‐FL alters proteostasis and induces TDP‐43 aggregation

Profiling of the muscle-specific dystroglycan interactome reveals the role of Hippo signaling in muscular dystrophy and age-dependent muscle atrophy

Myofibril and mitochondria morphogenesis are coordinated by a mechanical feedback mechanism in muscle

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