scholarly journals Natural History of a Mouse Model Overexpressing the Dp71 Dystrophin Isoform

2021 ◽  
Vol 22 (23) ◽  
pp. 12617
Author(s):  
Kenji Rowel Q. Lim ◽  
Md Nur Ahad Shah ◽  
Stanley Woo ◽  
Harry Wilton-Clark ◽  
Pavel Zhabyeyev ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Tibialis Anterior ◽  
Systolic Dysfunction ◽  
Dystrophin Gene ◽  
Multiple Promoters ◽  
Skeletal Muscle Weakness ◽  
Associated Proteins ◽  
History Of ◽  
Dmd Gene

Dystrophin is a 427 kDa protein that stabilizes muscle cell membranes through interactions with the cytoskeleton and various membrane-associated proteins. Loss of dystrophin as in Duchenne muscular dystrophy (DMD) causes progressive skeletal muscle weakness and cardiac dysfunction. Multiple promoters along the dystrophin gene (DMD) give rise to a number of shorter isoforms. Of interest is Dp71, a 71 kDa isoform implicated in DMD pathology by various animal and patient studies. Strong evidence supporting such a role for Dp71, however, is lacking. Here, we use del52;WT mice to understand how Dp71 overexpression affects skeletal and cardiac muscle phenotypes. Apart from the mouse Dmd gene, del52;WT mice are heterozygous for a full-length, exon 52-deleted human DMD transgene expected to only permit Dp71 expression in muscle. Thus, del52;WT mice overexpress Dp71 through both the human and murine dystrophin genes. We observed elevated Dp71 protein in del52;WT mice, significantly higher than wild-type in the heart but not the tibialis anterior. Moreover, del52;WT mice had generally normal skeletal muscle but impaired cardiac function, exhibiting significant systolic dysfunction as early as 3 months. No histological abnormalities were found in the tibialis anterior and heart. Our results suggest that Dp71 overexpression may have more detrimental effects on the heart than on skeletal muscles, providing insight into the role of Dp71 in DMD pathogenesis.

Characterisation of dystrophin during development of human skeletal muscle

Development ◽  
1992 ◽  
Vol 114 (2) ◽  
pp. 395-402 ◽  
Author(s):  
A. Clerk ◽  
P.N. Strong ◽  
C.A. Sewry
Keyword(s):  
Skeletal Muscle ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Human Skeletal Muscle ◽  
Gradual Increase ◽  
Differential Staining ◽  
Relative Molecular Mass ◽  
Adult Tissue ◽  
Dmd Gene

Dystrophin, the 427 × 10(3) Mr product of the Duchenne muscular dystrophy (DMD) gene, was studied in human foetal skeletal muscle from 9 to 26 weeks of gestation. Dystrophin could be detected from at least 9 weeks of gestation at the sarcolemmal membrane of most myotubes, though there was differential staining with antibodies raised to various regions of the protein. Dystrophin immunostaining increased and became more uniform with age and by 26 weeks of gestation there was intense sarcolemmal staining of all myotubes. On a Western blot, a doublet of smaller relative molecular mass than that seen in adult tissue was detected in all foetuses studied. There was a gradual increase in abundance of the upper band from 9 to 26 weeks, and the lower band, although present in low amounts in young foetuses, increased significantly between 20 and 26 weeks of gestation. These data indicate that there are several specific isoforms of dystrophin present in developing skeletal muscle, though the role of these is unknown.

Expression levels of RyR1 and RyR3 control resting free Ca2+ in skeletal muscle

2005 ◽  
Vol 288 (3) ◽  
pp. C640-C649 ◽  
Author(s):  
Claudio F. Perez ◽  
José R. López ◽  
Paul D. Allen
Keyword(s):  
Skeletal Muscle ◽  
Ryanodine Receptor ◽  
Tibialis Anterior ◽  
Muscle Fibers ◽  
Expression Levels ◽  
Cultured Myotubes ◽  
Increased Sensitivity ◽  
Type 3 ◽  
Different Levels

To better understand the role of the transient expression of ryanodine receptor (RyR) type 3 (RyR3) on Ca2+ homeostasis during the development of skeletal muscle, we have analyzed the effect of expression levels of RyR3 and RyR1 on the overall physiology of cultured myotubes and muscle fibers. Dyspedic myotubes were infected with RyR1 or RyR3 containing virions at 0.2, 0.4, 1.0, and 4.0 moieties of infection (MOI), and analysis of their pattern of expression, caffeine sensitivity, and resting free Ca2+ concentration ([Ca2+]r) was performed. Although increased MOI resulted in increased expression of each receptor isoform, it did not significantly affect the immunopattern of RyRs or the expression levels of calsequestrin, triadin, or FKBP-12. Interestingly, myotubes expressing RyR3 always had significantly higher [Ca2+]r and lower caffeine EC50 than did cells expressing RyR1. Although some of the increased sensitivity of RyR3 to caffeine could be attributed to the higher [Ca2+]r in RyR3-expressing cells, studies of [3H]ryanodine binding demonstrated intrinsic differences in caffeine sensitivity between RyR1 and RyR3. Tibialis anterior (TA) muscle fibers at different stages of postnatal development exhibited a transient increase in [Ca2+]r coordinately with their level of RyR3 expression. Similarly, adult soleus fibers, which also express RyR3, had higher [Ca2+]r than did adult TA fibers, which exclusively express RyR1. These data show that in skeletal muscle, RyR3 increases [Ca2+]r more than RyR1 does at any expression level. These data suggest that the coexpression of RyR1 and RyR3 at different levels may constitute a novel mechanism by which to regulate [Ca2+]r in skeletal muscle.

scholarly journals Role of miR-200c in Myogenic Differentiation Impairment via p66Shc: Implication in Skeletal Muscle Regeneration of Dystrophic mdx Mice

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Marco D’Agostino ◽  
Alessio Torcinaro ◽  
Luca Madaro ◽  
Lorenza Marchetti ◽  
Sara Sileno ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Myogenic Differentiation ◽  
Dystrophin Gene ◽  
Muscle Differentiation ◽  
Skeletal Muscle Regeneration ◽  
Mdx Mice ◽  
Pathological Disease ◽  
Dependent Mechanism

Duchenne muscular dystrophy (DMD) is a genetic disease associated with mutations of Dystrophin gene that regulate myofiber integrity and muscle degeneration, characterized by oxidative stress increase. We previously published that reactive oxygen species (ROS) induce miR-200c that is responsible for apoptosis and senescence. Moreover, we demonstrated that miR-200c increases ROS production and phosphorylates p66Shc in Ser-36. p66Shc plays an important role in muscle differentiation; we previously showed that p66Shc−/− muscle satellite cells display lower oxidative stress levels and higher proliferation rate and differentiated faster than wild-type (wt) cells. Moreover, myogenic conversion, induced by MyoD overexpression, is more efficient in p66Shc−/− fibroblasts compared to wt cells. Herein, we report that miR-200c overexpression in cultured myoblasts impairs skeletal muscle differentiation. Further, its overexpression in differentiated myotubes decreases differentiation indexes. Moreover, anti-miR-200c treatment ameliorates myogenic differentiation. In keeping, we found that miR-200c and p66Shc Ser-36 phosphorylation increase in mdx muscles. In conclusion, miR-200c inhibits muscle differentiation, whereas its inhibition ameliorates differentiation and its expression levels are increased in mdx mice and in differentiated human myoblasts of DMD. Therefore, miR-200c might be responsible for muscle wasting and myotube loss, most probably via a p66Shc-dependent mechanism in a pathological disease such as DMD.

scholarly journals Restoration of dystrophin-associated proteins in skeletal muscle of mdx mice transgenic for dystrophin gene

FEBS Letters ◽  
1993 ◽  
Vol 320 (3) ◽  
pp. 276-280 ◽  
Author(s):  
Kiichiro Matsumura ◽  
Cheng Chi Lee ◽  
C.Thomas Caskey ◽  
Kevin P. Campbell
Keyword(s):  
Skeletal Muscle ◽  
Dystrophin Gene ◽  
Mdx Mice ◽  
Associated Proteins

scholarly journals A role of tensin in skeletal-muscle regeneration

2001 ◽  
Vol 356 (3) ◽  
pp. 737-745 ◽  
Author(s):  
Akiko ISHII ◽  
S. Hao LO
Keyword(s):  
Skeletal Muscle ◽  
Knockout Mice ◽  
Muscle Regeneration ◽  
Fold Increase ◽  
Skeletal Muscle Regeneration ◽  
Muscle Fibres ◽  
Double Labelling ◽  
Wild Type ◽  
Associated Proteins

Regeneration of skeletal muscle requires the activation, proliferation, differentiation and fusion of satellite cells to generate new muscle fibres. This study was designed to determine the role of tensin in this process. Cardiotoxin was used to induce regeneration in the anterior tibial muscles of tensin-knockout and wild-type mice. From histological analysis, we found that the regeneration process lasted longer in knockout than in wild-type mice. To investigate the mechanism involved in this delay, we examined each regeneration step in animals and cultured primary cells. We found fewer proliferating myogenic cells identified by bromodeoxyuridine and desmin double labelling in knockout mice on the first 2 days after injury. Expression of myosin, paxillin, dystrophin and dystrophin-associated proteins were delayed in knockout mice. Withdrawal from the cell cycle was less efficient in isolated knockout myoblasts, and the fusion capacity was reduced in these cells as well. These defects in regeneration most likely contributed to the 9-fold increase of centrally nucleated fibres occurring in the non-injected knockout mice. Our results demonstrated clearly that tensin plays a role in skeletal-muscle regeneration.

scholarly journals Impact of Intrinsic Muscle Weakness on Muscle–Bone Crosstalk in Osteogenesis Imperfecta

2021 ◽  
Vol 22 (9) ◽  
pp. 4963
Author(s):  
Victoria L. Gremminger ◽  
Charlotte L. Phillips
Keyword(s):  
Skeletal Muscle ◽  
Osteogenesis Imperfecta ◽  
Muscle Weakness ◽  
Muscle Function ◽  
Critical Role ◽  
Connective Tissue Disorder ◽  
Bone Fragility ◽  
Skeletal Muscle Function ◽  
Skeletal Muscle Weakness

Bone and muscle are highly synergistic tissues that communicate extensively via mechanotransduction and biochemical signaling. Osteogenesis imperfecta (OI) is a heritable connective tissue disorder of severe bone fragility and recently recognized skeletal muscle weakness. The presence of impaired bone and muscle in OI leads to a continuous cycle of altered muscle–bone crosstalk with weak muscles further compromising bone and vice versa. Currently, there is no cure for OI and understanding the pathogenesis of the skeletal muscle weakness in relation to the bone pathogenesis of OI in light of the critical role of muscle–bone crosstalk is essential to developing and identifying novel therapeutic targets and strategies for OI. This review will highlight how impaired skeletal muscle function contributes to the pathophysiology of OI and how this phenomenon further perpetuates bone fragility.

scholarly journals Sarcomere number regulation maintained after immobilization in desmin-null mouse skeletal muscle

2001 ◽  
Vol 204 (10) ◽  
pp. 1703-1710 ◽  
Author(s):  
S.B. Shah ◽  
D. Peters ◽  
K.A. Jordan ◽  
D.J. Milner ◽  
J. Friden ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Knockout Mice ◽  
Tibialis Anterior ◽  
Null Mouse ◽  
Wild Type ◽  
Optimal Arrangement ◽  
Hindlimb Muscles ◽  
Muscle Changes ◽  
Sarcomere Number

The serial sarcomere number of skeletal muscle changes in response to chronic length perturbation. The role of the intermediate filament desmin in regulating these changes was investigated by comparing the architectural adaptations of the tibialis anterior, extensor digitorum longus (EDL) and soleus from wild-type mice with those of homozygous desmin knockout mice after hindlimb immobilization. After 28 days, serial sarcomere number increased significantly in the lengthened wild-type tibialis anterior (by approximately 9 %) and EDL (by approximately 17 %). Surprisingly, muscles from desmin knockout mice also experienced significant serial remodeling, with the serial sarcomere number of the tibialis anterior increasing by approximately 10 % and that of the EDL by approximately 27 %. A consistent result was observed in the shortened soleus: a significant decrease in sarcomere number was observed in the muscles from both wild-type (approximately 26 %) and knockout (approximately 12 %) mice. Thus, although desmin is not essential for sarcomerogenesis or sarcomere subtraction in mouse hindlimb muscles, the results do suggest subtle differences in the nature of sarcomere number adaptation. We speculate that desmin may play a role in regulating the optimal arrangement of sarcomeres within the muscle or in sensing the magnitude of the immobilization effect itself.

scholarly journals Effects of microgravity on myogenic factor expressions during postnatal development of rat skeletal muscle

2002 ◽  
Vol 92 (5) ◽  
pp. 1936-1942 ◽  
Author(s):  
Manabu Inobe ◽  
Ikuko Inobe ◽  
Gregory R. Adams ◽  
Kenneth M. Baldwin ◽  
Shin'Ichi Takeda
Keyword(s):  
Skeletal Muscle ◽  
Postnatal Development ◽  
Tibialis Anterior ◽  
Skeletal Muscles ◽  
Medial Gastrocnemius ◽  
Rt Pcr ◽  
Specific Primers ◽  
Myogenic Factor ◽  
Semiquantitative Method

To clarify the role of gravity in the postnatal development of skeletal muscle, we exposed neonatal rats at 7 days of age to microgravity. After 16 days of spaceflight, tibialis anterior, plantaris, medial gastrocnemius, and soleus muscles were removed from the hindlimb musculature and examined for the expression of MyoD-family transcription factors such as MyoD, myogenin, and MRF4. For this purpose, we established a unique semiquantitative method, based on RT-PCR, using specific primers tagged with infrared fluorescence. The relative expression of MyoD in the tibialis anterior and plantaris muscles and that of myogenin in the plantaris and soleus muscles were significantly reduced ( P < 0.001) in the flight animals. In contrast, MRF4 expression was not changed in any muscle. These results suggest that MyoD and myogenin, but not MRF4, are sensitive to gravity-related stimuli in some skeletal muscles during postnatal development.

Elaborating the role of reflection and individual differences in the study of folk-economic beliefs

2018 ◽  
Vol 41 ◽  
Author(s):  
Kevin Arceneaux
Keyword(s):  
Decision Making ◽  
Individual Differences ◽  
Cognitive Processes ◽  
Evolutionary History ◽  
Behavioral Responses ◽  
History Of ◽  
Economic Beliefs

AbstractIntuitions guide decision-making, and looking to the evolutionary history of humans illuminates why some behavioral responses are more intuitive than others. Yet a place remains for cognitive processes to second-guess intuitive responses – that is, to be reflective – and individual differences abound in automatic, intuitive processing as well.

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