scholarly journals Rescue of skeletal muscle α-actin–null mice by cardiac (fetal) α-actin

2009 ◽  
Vol 185 (5) ◽  
pp. 903-915 ◽  
Author(s):  
Kristen J. Nowak ◽  
Gianina Ravenscroft ◽  
Connie Jackaman ◽  
Aleksandra Filipovska ◽  
Stefan M. Davies ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Locomotor Activity ◽  
Mouse Model ◽  
Old Age ◽  
Knockout Mice ◽  
Skeletal Muscles ◽  
Pathological Features ◽  
Congenital Myopathies ◽  
Functional Differences ◽  
Mouse Lines

Skeletal muscle α-actin (ACTA1) is the major actin in postnatal skeletal muscle. Mutations of ACTA1 cause mostly fatal congenital myopathies. Cardiac α-actin (ACTC) is the major striated actin in adult heart and fetal skeletal muscle. It is unknown why ACTC and ACTA1 expression switch during development. We investigated whether ACTC can replace ACTA1 in postnatal skeletal muscle. Two ACTC transgenic mouse lines were crossed with Acta1 knockout mice (which all die by 9 d after birth). Offspring resulting from the cross with the high expressing line survive to old age, and their skeletal muscles show no gross pathological features. The mice are not impaired on grip strength, rotarod, or locomotor activity. These findings indicate that ACTC is sufficiently similar to ACTA1 to produce adequate function in postnatal skeletal muscle. This raises the prospect that ACTC reactivation might provide a therapy for ACTA1 diseases. In addition, the mouse model will allow analysis of the precise functional differences between ACTA1 and ACTC.

scholarly journals Trim33 (Tif1γ) is not required for skeletal muscle development or regeneration but suppresses cholecystokinin expression

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Cassie A. Parks ◽  
Katherine Pak ◽  
Iago Pinal-Fernandez ◽  
Wilson Huang ◽  
Assia Derfoul ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cells ◽  
Knockout Mice ◽  
Muscle Regeneration ◽  
Skeletal Muscles ◽  
Muscle Development ◽  
Conditional Knockout ◽  
C2c12 Cells ◽  
Mouse Muscle ◽  
Muscle Histology

AbstractThe expression of Trim33 (Tif1γ) increases in skeletal muscles during regeneration and decreases upon maturation. Although Trim33 is required for the normal development of other tissues, its role in skeletal muscle is unknown. The current study aimed to define the role of Trim33 in muscle development and regeneration. We generated mice with muscle-specific conditional knockout of Trim33 by combining floxed Trim33 and Cre recombinase under the Pax7 promoter. Muscle regeneration was induced by injuring mouse muscles with cardiotoxin. We studied the consequences of Trim33 knockdown on viability, body weight, skeletal muscle histology, muscle regeneration, and gene expression. We also studied the effect of Trim33 silencing in satellite cells and the C2C12 mouse muscle cell line. Although Trim33 knockdown mice weighed less than control mice, their skeletal muscles were histologically unremarkable and regenerated normally following injury. Unexpectedly, RNAseq analysis revealed dramatically increased expression of cholecystokinin (CCK) in regenerating muscle from Trim33 knockout mice, satellite cells from Trim33 knockout mice, and C2C12 cells treated with Trim33 siRNA. Trim33 knockdown had no demonstrable effect on muscle differentiation or regeneration. However, Trim33 knockdown induced CCK expression in muscle, suggesting that suppression of CCK expression requires Trim33.

scholarly journals Requirement for PINCH in Skeletal Myoblast Differentiation

2021 ◽  
Author(s):  
Siyi Xie ◽  
Chushan Fang ◽  
Yujie Gao ◽  
Jie Yan ◽  
Lina Luo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Skeletal Muscles ◽  
Molecular Mechanisms ◽  
Myogenic Differentiation ◽  
Critical Role ◽  
The Body ◽  
Myoblast Differentiation ◽  
Skeletal Myogenesis ◽  
Congenital Myopathies

Abstract Background: Skeletal muscle is composed of bundles of myofibers ensheathed by extracellular matrix networks. Malformation of skeletal muscle during embryonic development results in congenital myopathies. Disease mechanisms of congenital myopathies remain unclear. PINCH, an adaptor of focal adhesion complex, plays essential roles in multiple cellular processes and organogenesis. Elucidation of the molecular mechanisms underlying skeletal myogenesis will offer new insights into pathogenesis of myopathies.Methods: We generated muscle-specific PINCH knock-out mice to study the functional role of PINCH in skeletal myogenesis. Histologic and Transmission Electron Microscopy analysis demonstrated that Impaired myogenic differentiation and maturation in mice with PINCH1 being ablated in skeletal muscle progenitors, and Ablation of PINCH1 and PINCH2 resulted in reduced size of muscle fibers and impaired multinucleation; Cell culture and immunostaining showed that defects in myoblast fusion and cytoskeleton assembly in PINCH double mutant mice; Western blotting showed that defects in expression of cytoskeleton proteins and proteins involved in myogenesis in DMUT skeletal muscles.Results: Double ablation of PINCH1 and PINCH2 resulted in early postnatal lethality with reduced size of skeletal muscles and detachment of diaphragm muscles from the body wall. Myofibers of PINCH mutant myofibers failed to undergo multinucleation and exhibited disrupted sarcomere structures. The mutant myoblasts in culture were able to adhere to newly formed myotubes, but impeded in cell fusion and subsequent sarcomere genesis and cytoskeleton organization. Consistent with this, expression of integrin β1 and some cytoskeleton proteins, and phosphorylation of ERK and AKT were significantly reduced in PINCH mutants. Expression of MRF4, the most highly expressed myogenic factor at late stages of myogenesis, was abolished in PINCH mutants, that could contribute to observed phenotypes. In addition, mice with PINCH1 being ablated in myogenic progenitors exhibited only mild centronuclear myopathic changes, suggesting a compensatory role of PINCH2 in myogenic differentiation, indicating a critical role of PINCH proteins in myogenic differentiation.Conclusion: Our results demonstrated an essential role of PINCH in skeletal myogenic differentiation.

Endothelial NOS is main mediator for shear stress-dependent angiogenesis in skeletal muscle after prazosin administration

2004 ◽  
Vol 287 (5) ◽  
pp. H2300-H2308 ◽  
Author(s):  
Oliver Baum ◽  
Luis Da Silva-Azevedo ◽  
Gregor Willerding ◽  
Achim Wöckel ◽  
Gerit Planitzer ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Shear Stress ◽  
Wall Shear Stress ◽  
Knockout Mice ◽  
Skeletal Muscles ◽  
Capillary Density ◽  
Enos Expression ◽  
Wall Shear ◽  
Stress Dependent ◽  
Endothelial Nitric Oxide

The increase of wall shear stress in capillaries by oral administration of the α1-adrenergic receptor antagonist prazosin induces angiogenesis in skeletal muscles. Because endothelial nitric oxide synthase (eNOS) is upregulated in response to elevated wall shear stress, we investigated the relevance of eNOS for prazosin-induced angiogenesis in skeletal muscles. Prazosin and/or the NOS inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) were given to C57BL/6 wild-type mice and eNOS-knockout mice for 14 days. The capillary-to-fiber (C/F) ratio and capillary density (CD; no. of capillaries/mm2) were determined in frozen sections from extensor digitorum longus (EDL) muscles of these mice. Immunoblotting was performed to quantify eNOS expression in endothelial cells isolated from skeletal muscles, whereas VEGF (after precipitation with heparin-agarose) and neuronal NOS (nNOS) concentrations were determined in EDL solubilizates. In EDL muscles of C57BL/6 mice treated for 14 days, the C/F ratio was 28% higher after prazosin administration and 11% higher after prazosin and l-NAME feeding, whereas the CD increased by 21 and 13%, respectively. The C/F ratio was highest after day 4 of prazosin treatment and decreased gradually to almost constant values after day 8. Prazosin administration led to elevation of eNOS expression. VEGF levels were lowest at day 4, whereas nNOS values decreased after day 8. In EDL muscles of eNOS-knockout mice, no significant changes in C/F ratio, CD, or VEGF and nNOS expression were observed in response to prazosin administration. Our data suggest that the presence of eNOS is essential for prazosin-induced angiogenesis in skeletal muscle, albeit other signaling molecules might partially compensate for or contribute to this angiogenic activity. Furthermore, subsequent remodeling of the capillary system accompanied by sequential downregulation of VEGF and nNOS in skeletal muscle fibers characterizes shear stress-dependent angiogenesis.

ATP-sensitive K+ channel-mediated glucose uptake is independent of IRS-1/phosphatidylinositol 3-kinase signaling

2003 ◽  
Vol 285 (6) ◽  
pp. E1289-E1296 ◽  
Author(s):  
Kohtaro Minami ◽  
Mizuo Morita ◽  
Atsunori Saraya ◽  
Hideki Yano ◽  
Yasuo Terauchi ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Receptor ◽  
Glucose Uptake ◽  
Knockout Mice ◽  
Skeletal Muscles ◽  
K Channel ◽  
Phosphatidylinositol 3 Kinase ◽  
Double Knockout ◽  
Phosphatidylinositol 3

We previously found that disruption of Kir6.2-containing ATP-sensitive K+ (Katp) channels increases glucose uptake in skeletal muscle, but the mechanism is not clear. In the present study, we generated knockout mice lacking both Kir6.2 and insulin receptor substrate-1 (IRS-1). Because IRS-1 is the major substrate of insulin receptor kinase, we expected disruption of the IRS-1 gene to reduce glucose uptake in Kir6.2 knockout mice. However, the double-knockout mice do not develop insulin resistance or glucose intolerance. An insulin tolerance test reveals the glucose-lowering effect of exogenous insulin in double-knockout mice and in Kir6.2 knockout mice to be similarly enhanced compared with wild-type mice. The basal 2-deoxyglucose uptake rate in skeletal muscle of double-knockout mice is increased similarly to the rate in Kir6.2 knockout mice. Accordingly, disruption of the IRS-1 gene affects neither systemic insulin sensitivity nor glucose uptake in skeletal muscles of Kir6.2-deficient mice. In addition, no significant changes were observed in phosphatidylinositol 3-kinase (PI3K) activity and its downstream signal in skeletal muscle due to lack of the Kir6.2 gene. Disruption of Kir6.2-containing Katp channels clearly protects against IRS-1-associated insulin resistance by increasing glucose uptake in skeletal muscles by a mechanism separate from the IRS-1/PI3K pathway.

MECHANISM OF VARIABILITY REDUCTION IN THE SYSTEM OF SKELETAL MUSCLE MANAGEMENT IN ATHLETES ACCORDING TO THE PRINCIPLE OF FUNCTIONAL SYNERGY FORMATION

2019 ◽  
pp. 95-104
Author(s):  
S.A. Moiseev
Keyword(s):  
Skeletal Muscle ◽  
Skeletal Muscles ◽  
Anterior Part ◽  
Movement Control ◽  
Small Variation ◽  
Deltoid Muscle ◽  
Simultaneous Recording ◽  
Muscle Synergy ◽  
Statistical Parameters ◽  
Left Limb

The question of physiological function variability is of great theoretical interest, since it is a part of the theory of human voluntary movement control. The skeletal muscle control system should probably have a mechanism to reduce or limit the range of its possible variations. Presumably, the organization of the motor system elements according to the principle of muscular synergy is of such a nature. The objective of the work is to study variations and signs of the coordinated bioelectric activity of skeletal muscles in one of the resulting archery phases. Materials and Methods. The study enrolled 5 highly qualified sportsmen (Master of Sport, International Master of Sport). Archers shot 10 series of 3 shots, target distance 18 m, indoors. Simultaneous recording of electrical activity of 12 skeletal muscles of the upper limb girdle and a 3D video sequence was made. The authors analyzed indicators of distribution, descriptive and variation statistics for grouped data. Multiple regression analysis was used to identify signs of consistent muscle activity. Results. Variability magnitudes, characterized by statistical parameters, established for the turn-off-peak characteristics of various muscles, did not have an explicit dependence. Muscles with relatively high scattering parameters in terms of the EMG average amplitude could have a small variation in the average number of EMG turns. The radial flexor of the left hand wrist was a part of muscular synergy in 90 % of cases, the anterior part of the left limb deltoid muscle – in 80 % of cases, the lower and upper beams of the right and left cowl muscle – in 70 % of cases. Other muscles under consideration were their part in less than 60 % of cases. Conclusion. The system of skeletal muscles that are actively involved in the resulting phases of precision movement can be controlled according to the mechanism of functional synergy formation, which probably helps to reduce the range of possible variations in the parameters of muscle electroactivity. Keywords: variability, archery, electromyography, coordination structure, muscle synergy. Вопрос вариативности физиологических функций представляет интерес в теоретическом плане, поскольку является частью теории управления произвольными движениями человека. Система управления скелетными мышцами, вероятно, должна иметь механизм, позволяющий сократить или ограничить диапазон возможных ее вариаций. Таковым, предположительно, является организация элементов моторной системы по принципу мышечных синергий. Цель работы – изучение вариаций и признаков согласованной биоэлектрической активности скелетных мышц в одной из результирующих фаз выстрела из лука. Материалы и методы. В исследованиях приняли участие 5 высококвалифицированных спортсменов (МС, МСМК). Лучники выполняли 10 серий по 3 выстрела с дистанции 18 м в крытом помещении. Производилась синхронная регистрация электрической активности 12 скелетных мышц верхнего плечевого пояса и 3D-видеоряда. Анализировались показатели распределения, описательной и вариационной статистики для сгруппированных данных. Для выявления признаков согласованной активности мышц применялся множественный регрессионный анализ. Результаты. Величины вариативности, характеризуемые статистическими параметрами, установленные для турн-аплитудных характеристик различных мышц, не имели явной зависимости. Мышцы, имеющие относительно высокие параметры разброса значений по показателю средней амплитуды ЭМГ, могли иметь небольшую вариативность среднего числа турнов ЭМГ. Лучевой сгибатель кисти левой руки являлся частью мышечной синергии в 90 % случаев, передняя часть дельтовидной мышцы левой конечности – в 80 %, нижние и верхние пучки трапециевидной мышцы правой и левой сторон – в 70 %. Другие исследуемые мышцы являлись их частью в менее чем 60 % случаев. Выводы. Управление системой скелетных мышц, принимающих активное участие в реализации одной из результирующих фаз точностного движения, может осуществляться по механизму образования функциональных синергий, что, вероятно, способствует снижению диапазона возможных вариаций параметров электроактивности мышц. Ключевые слова: вариативность, стрельба из лука, электромиография, координационная структура, мышечные синергии.

scholarly journals Bioengineered in vitro skeletal muscles as new tools for muscular dystrophies preclinical studies

2021 ◽  
Vol 12 ◽  
pp. 204173142098133
Author(s):  
Juan M. Fernández-Costa ◽  
Xiomara Fernández-Garibay ◽  
Ferran Velasco-Mallorquí ◽  
Javier Ramón-Azcón
Keyword(s):  
Skeletal Muscle ◽  
Tissue Engineering ◽  
Electrical Stimulation ◽  
Skeletal Muscles ◽  
Screening Tools ◽  
Muscular Dystrophies ◽  
Preclinical Studies ◽  
Technological Advances ◽  
Topographical Cues

Muscular dystrophies are a group of highly disabling disorders that share degenerative muscle weakness and wasting as common symptoms. To date, there is not an effective cure for these diseases. In the last years, bioengineered tissues have emerged as powerful tools for preclinical studies. In this review, we summarize the recent technological advances in skeletal muscle tissue engineering. We identify several ground-breaking techniques to fabricate in vitro bioartificial muscles. Accumulating evidence shows that scaffold-based tissue engineering provides topographical cues that enhance the viability and maturation of skeletal muscle. Functional bioartificial muscles have been developed using human myoblasts. These tissues accurately responded to electrical and biological stimulation. Moreover, advanced drug screening tools can be fabricated integrating these tissues in electrical stimulation platforms. However, more work introducing patient-derived cells and integrating these tissues in microdevices is needed to promote the clinical translation of bioengineered skeletal muscle as preclinical tools for muscular dystrophies.

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