scholarly journals Drosophila model of myosin myopathy rescued by overexpression of a TRIM-protein family member

2018 ◽  
Vol 115 (28) ◽  
pp. E6566-E6575 ◽  
Author(s):  
Martin Dahl-Halvarsson ◽  
Montse Olive ◽  
Malgorzata Pokrzywa ◽  
Katarina Ejeskär ◽  
Ruth H. Palmer ◽  
...  
Keyword(s):  
Molecular Motor ◽  
Body Movement ◽  
Muscle Disease ◽  
Activity Levels ◽  
Distal Myopathy ◽  
Functional Impairments ◽  
Larval Body ◽  
Genomic Engineering ◽  
Leg Muscles ◽  
Body Wall Muscles

Myosin is a molecular motor indispensable for body movement and heart contractility. Apart from pure cardiomyopathy, mutations in MYH7 encoding slow/β-cardiac myosin heavy chain also cause skeletal muscle disease with or without cardiac involvement. Mutations within the α-helical rod domain of MYH7 are mainly associated with Laing distal myopathy. To investigate the mechanisms underlying the pathology of the recurrent causative MYH7 mutation (K1729del), we have developed a Drosophila melanogaster model of Laing distal myopathy by genomic engineering of the Drosophila Mhc locus. Homozygous MhcK1728del animals die during larval/pupal stages, and both homozygous and heterozygous larvae display reduced muscle function. Flies expressing only MhcK1728del in indirect flight and jump muscles, and heterozygous MhcK1728del animals, were flightless, with reduced movement and decreased lifespan. Sarcomeres of MhcK1728del mutant indirect flight muscles and larval body wall muscles were disrupted with clearly disorganized muscle filaments. Homozygous MhcK1728del larvae also demonstrated structural and functional impairments in heart muscle, which were not observed in heterozygous animals, indicating a dose-dependent effect of the mutated allele. The impaired jump and flight ability and the myopathy of indirect flight and leg muscles associated with MhcK1728del were fully suppressed by expression of Abba/Thin, an E3-ligase that is essential for maintaining sarcomere integrity. This model of Laing distal myopathy in Drosophila recapitulates certain morphological phenotypic features seen in Laing distal myopathy patients with the recurrent K1729del mutation. Our observations that Abba/Thin modulates these phenotypes suggest that manipulation of Abba/Thin activity levels may be beneficial in Laing distal myopathy.

scholarly journals Impaired muscle morphology in a Drosophila model of myosin storage myopathy was supressed by overexpression of an E3 ubiquitin ligase

2020 ◽  
Vol 13 (12) ◽  
pp. dmm047886
Author(s):  
Martin Dahl-Halvarsson ◽  
Montse Olive ◽  
Malgorzata Pokrzywa ◽  
Michaela Norum ◽  
Katarina Ejeskär ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Mutant Allele ◽  
Body Movement ◽  
E3 Ubiquitin Ligase ◽  
Ubiquitin Proteasome System ◽  
Muscle Disease ◽  
Muscle Morphology ◽  
Severe Impairment ◽  
Myosin Storage Myopathy ◽  
The Impact

ABSTRACTMyosin is vital for body movement and heart contractility. Mutations in MYH7, encoding slow/β-cardiac myosin heavy chain, are an important cause of hypertrophic and dilated cardiomyopathy, as well as skeletal muscle disease. A dominant missense mutation (R1845W) in MYH7 has been reported in several unrelated cases of myosin storage myopathy. We have developed a Drosophila model for a myosin storage myopathy in order to investigate the dose-dependent mechanisms underlying the pathological roles of the R1845W mutation. This study shows that a higher expression level of the mutated allele is concomitant with severe impairment of muscle function and progressively disrupted muscle morphology. The impaired muscle morphology associated with the mutant allele was suppressed by expression of Thin (herein referred to as Abba), an E3 ubiquitin ligase. This Drosophila model recapitulates pathological features seen in myopathy patients with the R1845W mutation and severe ultrastructural abnormalities, including extensive loss of thick filaments with selective A-band loss, and preservation of I-band and Z-disks were observed in indirect flight muscles of flies with exclusive expression of mutant myosin. Furthermore, the impaired muscle morphology associated with the mutant allele was suppressed by expression of Abba. These findings suggest that modification of the ubiquitin proteasome system may be beneficial in myosin storage myopathy by reducing the impact of MYH7 mutation in patients.

Phenotypic behavior of caveolin-3 R26Q, a mutant associated with hyperCKemia, distal myopathy, and rippling muscle disease

2003 ◽  
Vol 285 (5) ◽  
pp. C1150-C1160 ◽  
Author(s):  
Federica Sotgia ◽  
Scott E. Woodman ◽  
Gloria Bonuccelli ◽  
Franco Capozza ◽  
Carlo Minetti ◽  
...  
Keyword(s):  
Golgi Complex ◽  
Cell Function ◽  
Cultured Cells ◽  
Dominant Negative ◽  
Muscle Disease ◽  
Mutant Protein ◽  
Dominant Negative Effect ◽  
Distal Myopathy ◽  
Wild Type ◽  
Disease Phenotypes

Four different phenotypes have been associated with CAV3 mutations: limb girdle muscular dystrophy-1C (LGMD-1C), rippling muscle disease (RMD), and distal myopathy (DM), as well as idiopathic and familial hyperCKemia (HCK). Detailed molecular characterization of two caveolin-3 mutations (P104L and ΔTFT), associated with LGMD-1C, shows them to impart a dominant-negative effect on wild-type caveolin-3, rendering it dysfunctional through sequestration in the Golgi complex. Interestingly, substitution of glutamine for arginine at amino acid position 26 (R26Q) of caveolin-3 is associated not only with RMD but also with DM and HCK. However, the phenotypic behavior of the caveolin-3 R26Q mutation has never been evaluated in cultured cells. Thus we characterized the cellular and molecular properties of the R26Q mutant protein to better understand how this mutation can manifest as such distinct disease phenotypes. Here, we show that the caveolin-3 R26Q mutant is mostly retained at the level of the Golgi complex. The caveolin-3 R26Q mutant formed oligomers of a much larger size than wild-type caveolin-3 and was excluded from caveolae-enriched membranes. However, caveolin-3 R26Q did not behave in a dominant-negative fashion when coexpressed with wild-type caveolin-3. Thus the R26Q mutation behaves differently from other caveolin-3 mutations (P104L and ΔTFT) that have been previously characterized. These data provide a possible explanation for the scope of the various disease phenotypes associated with the caveolin-3 R26Q mutation. We propose a haploinsufficiency model in which reduced levels of wild-type caveolin-3, although not rendered dysfunctional due to the caveolin-3 R26Q mutant protein, are insufficient for normal muscle cell function.

scholarly journals Novel model of distal myopathy caused by the myosin rod mutation R1500P disrupts acto-myosin binding

2019 ◽  
Author(s):  
Genevieve C. K. Wilson ◽  
Ada Buvoli ◽  
Massimo Buvoli ◽  
Kathleen C. Woulfe ◽  
Lori A. Walker ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Structure And Function ◽  
Muscle Disease ◽  
Therapeutic Interventions ◽  
Small Subset ◽  
Histological Structure ◽  
Distal Myopathy ◽  
Myosin Binding ◽  
And Function ◽  
Myosin Rod

AbstractIntroductionMore than 400 mutations in β-myosin, a slow myosin motor, can cause both cardiac and skeletal myopathy in humans. A small subset of these mutations, mostly located in the myosin rod, leads to a progressive skeletal muscle disease known as Laing distal myopathy (MPD1). While this disease has previously been studied using a variety of systems, it has never been studied in the mammalian muscle environment. Here, we describe a mouse model for the MPD1-causing mutation R1500P to elucidate disease pathogenesis and to act as a future platform for testing therapeutic interventions.MethodsBecause mice have very few slow skeletal muscles compared to humans, we generated mice expressing the β-myosin R1500P mutation or WT β-myosin in fast skeletal muscle fibers and determined the structural and functional consequences of the R1500P mutation.ResultsThe mutant R1500P myosin affects both muscle histological structure and function and the mice exhibit a number of the histological hallmarks that are often identified in patients with MPD1. Furthermore, R1500P mice show decreased muscle strength and endurance, as well as ultrastructural abnormalities in the SR & t-tubules. Somewhat surprisingly because of its location in the rod, the R1500P mutation weakens acto-myosin binding by affecting cross-bridge detachment rate.ConclusionsWhile each group of MPD1-causing mutations most likely operates through distinct mechanisms, our model provides new insight into how a mutation in the rod domain impacts muscle structure and function and leads to disease.

scholarly journals Temporal contribution of body movement to very long-term heart rate variability in humans

2000 ◽  
Vol 278 (4) ◽  
pp. H1035-H1041 ◽  
Author(s):  
Naoko Aoyagi ◽  
Kyoko Ohashi ◽  
Shinji Tomono ◽  
Yoshiharu Yamamoto
Keyword(s):  
Heart Rate ◽  
Heart Rate Variability ◽  
Wigner Distribution ◽  
Body Movement ◽  
Ambulatory Monitoring ◽  
Coarse Graining ◽  
Single Subject ◽  
Activity Levels ◽  
Time Frequency

A newly developed, very long-term (∼7 days) ambulatory monitoring system for assessing beat-to-beat heart rate variability (HRV) and body movements (BM) was used to study the mechanism(s) responsible for the long-period oscillation in human HRV. Data continuously collected from five healthy subjects were analyzed by 1) standard auto- and cross-spectral techniques, 2) a cross-Wigner distribution (WD; a time-frequency analysis) between BM and HRV for 10-s averaged data, and 3) coarse-graining spectral analysis for 600 successive cardiac cycles. The results showed 1) a clear circadian rhythm in HRV and BM, 2) a 1/ f β-type spectrum in HRV and BM at ultradian frequencies, and 3) coherent relationships between BM and HRV only at specific ultradian as well as circadian frequencies, indicated by significant ( P < 0.05) levels of the squared coherence and temporal localizations of the covariance between BM and HRV in the cross-WD. In a single subject, an instance in which the behavioral (mean BM) and autonomic [HRV power >0.15 Hz and mean heart rate (HR)] rhythmicities were dissociated occurred when the individual had an irregular daily life. It was concluded that the long-term HRV in normal humans contained persistent oscillations synchronized with those of BM at ultradian frequencies but could not be explained exclusively by activity levels of the subjects.

Sexual dimorphism of the cuticle and body-wall muscle in free-living mycophagous nematodes

2019 ◽  
Vol 97 (6) ◽  
pp. 510-515 ◽  
Author(s):  
T. Ekino ◽  
T. Yoshiga ◽  
Y. Takeuchi-Kaneko ◽  
Y. Ichihara ◽  
N. Kanzaki
Keyword(s):  
Sexual Dimorphism ◽  
Body Wall ◽  
Body Movement ◽  
Structural Components ◽  
Muscle Area ◽  
Cross Sectional ◽  
Total Cross Sectional Area ◽  
Body Wall Muscles ◽  
Nematode Cuticle ◽  
Cuticle Thickness

Sexual dimorphism in motility-related traits is widespread among animals, including several species of Nematoda. However, no study has examined motility-related structural components and compared them between sexes. We examined the motility-related components in four species: Bursaphelenchus conicaudatus Kanzaki, Tsuda and Futai, 2000; Bursaphelenchus rainulfi Braasch and Burgermeister, 2002; Bursaphelenchus doui Braasch, Gu, Burgermeister and Zhang, 2005; Parasitaphelenchus costati Kanzaki, Ekino, Ide, Masuya and Degawa, 2018. We measured the structure and amount of cuticle and body-wall muscles and estimated their relationship to body diameter or total cross-sectional area. Although no structural differences were observed in muscle, the relevant muscle area of B. doui and P. costati was significantly smaller in females than in males. This difference was greatest in P. costati. In all but B. doui, the relative cuticle thickness was significantly smaller in females than in males. Furthermore, only P. costati females had no striated basal zones in their cuticles; these are thought to be cross-linked proteins that provide strength to nematode cuticle during body movement. These results indicate that sexual dimorphism in motility-related structural components is present in P. costati and that females invest less energy in the components than do males.

wingless is required for the formation of a subset of muscle founder cells during Drosophila embryogenesis

Development ◽  
1995 ◽  
Vol 121 (11) ◽  
pp. 3829-3837 ◽  
Author(s):  
M.K. Baylies ◽  
A. Martinez Arias ◽  
M. Bate
Keyword(s):  
Molecular Mechanisms ◽  
Expression System ◽  
Larval Body ◽  
Signalling Molecule ◽  
Segment Polarity ◽  
In The Wild ◽  
Body Wall Muscles ◽  
Founder Cells ◽  
Inductive Signal

The final pattern of the Drosophila larval body wall muscles depends critically on the prior segregation of muscle founder cells. We would like to understand the underlying molecular mechanisms which ensure the precise allocation and placement of these muscle founder cells. We have begun our analysis by examining the role of the segment polarity genes, known to be involved in the patterning of the ectoderm. Mutations in only one member of this class, wingless (wg), lead to the complete loss of a subset of muscle founder cells characterised by the expression of S59. Using the GAL4-targetted expression system, we find that Wingless, a secreted glycoprotein and well characterized signalling molecule, acts directly on the mesoderm to ensure the formation of S59-expressing founder cells. Moreover, we present evidence that Wg can signal across germ layers and that, in the wild-type embryo, Wg from the ectoderm could constitute an inductive signal for the initiation of the development of a subset of somatic muscles.

scholarly journals Dystroglycan and Protein O-Mannosyltransferases 1 and 2 Are Required to Maintain Integrity of Drosophila Larval Muscles

2007 ◽  
Vol 18 (12) ◽  
pp. 4721-4730 ◽  
Author(s):  
Nicola Haines ◽  
Sara Seabrooke ◽  
Bryan A. Stewart
Keyword(s):  
Muscular Dystrophy ◽  
Muscle Contraction ◽  
Body Wall ◽  
Membrane Resistance ◽  
Muscle Membrane ◽  
Muscle Attachment ◽  
Larval Body ◽  
Genes Encoding ◽  
Body Wall Muscles ◽  
Drosophila Mutant

In vertebrates, mutations in Protein O-mannosyltransferase1 (POMT1) or POMT2 are associated with muscular dystrophy due to a requirement for O-linked mannose glycans on the Dystroglycan (Dg) protein. In this study we examine larval body wall muscles of Drosophila mutant for Dg, or RNA interference knockdown for Dg and find defects in muscle attachment, altered muscle contraction, and a change in muscle membrane resistance. To determine if POMTs are required for Dg function in Drosophila, we examine larvae mutant for genes encoding POMT1 or POMT2. Larvae mutant for either POMT, or doubly mutant for both, show muscle attachment and muscle contraction phenotypes identical to those associated with reduced Dg function, consistent with a requirement for O-linked mannose on Drosophila Dg. Together these data establish a central role for Dg in maintaining integrity in Drosophila larval muscles and demonstrate the importance of glycosylation to Dg function in Drosophila. This study opens the possibility of using Drosophila to investigate muscular dystrophy.

Electrophysiological Recording from Drosophila Larval Body-Wall Muscles

2010 ◽  
Vol 2010 (9) ◽  
pp. pdb.prot5487-pdb.prot5487 ◽  
Author(s):  
B. Zhang ◽  
B. Stewart
Keyword(s):  
Body Wall ◽  
Electrophysiological Recording ◽  
Larval Body ◽  
Body Wall Muscles
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