scholarly journals Downsizing the molecular spring of the giant protein titin reveals that skeletal muscle titin determines passive stiffness and drives longitudinal hypertrophy

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Ambjorn Brynnel ◽  
Yaeren Hernandez ◽  
Balazs Kiss ◽  
Johan Lindqvist ◽  
Maya Adler ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mouse Model ◽  
Striated Muscle ◽  
Super Resolution ◽  
Editorial Note ◽  
Passive Stiffness ◽  
Thin Filaments ◽  
In Series ◽  
Active Force Generation

Titin, the largest protein known, forms an elastic myofilament in the striated muscle sarcomere. To establish titin’s contribution to skeletal muscle passive stiffness, relative to that of the extracellular matrix, a mouse model was created in which titin’s molecular spring region was shortened by deleting 47 exons, the TtnΔ112-158 model. RNA sequencing and super-resolution microscopy predicts a much stiffer titin molecule. Mechanical studies with this novel mouse model support that titin is the main determinant of skeletal muscle passive stiffness. Unexpectedly, the in vivo sarcomere length working range was shifted to shorter lengths in TtnΔ112-158 mice, due to a ~ 30% increase in the number of sarcomeres in series (longitudinal hypertrophy). The expected effect of this shift on active force generation was minimized through a shortening of thin filaments that was discovered in TtnΔ112-158 mice. Thus, skeletal muscle titin is the dominant determinant of physiological passive stiffness and drives longitudinal hypertrophy.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (<xref ref-type="decision-letter" rid="SA1">see decision letter</xref>).

Super-resolution ultrasound imaging for in vivo microvasculature assessment in acute kidney injury mouse model

2019 ◽  
Vol 145 (3) ◽  
pp. 1859-1859
Author(s):  
Qiyang Chen ◽  
Brittney M. Rush ◽  
Jaesok Yu ◽  
Roderick Tan ◽  
Kang Kim
Keyword(s):  
Acute Kidney Injury ◽  
Mouse Model ◽  
Ultrasound Imaging ◽  
Kidney Injury ◽  
Super Resolution

scholarly journals THE ULTRASTRUCTURE OF FROG VENTRICULAR CARDIAC MUSCLE AND ITS RELATIONSHIP TO MECHANISMS OF EXCITATION-CONTRACTION COUPLING

1968 ◽  
Vol 38 (1) ◽  
pp. 99-114 ◽  
Author(s):  
Nancy A. Staley ◽  
Ellis S. Benson
Keyword(s):  
Skeletal Muscle ◽  
Cardiac Muscle ◽  
Striated Muscle ◽  
Structural Features ◽  
Mammalian Skeletal Muscle ◽  
Striated Muscles ◽  
Thin Filaments ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Dense Granules

Frog ventricular cardiac muscle has structural features which set it apart from frog and mammalian skeletal muscle and mammalian cardiac muscle. In describing these differences, our attention focused chiefly on the distribution of cellular membranes. Abundant inter cellular clefts, the absence of tranverse tubules, and the paucity of sarcotubules, together with exceedingly small cell diameters (less than 5 µ), support the suggestion that the mechanism of excitation-contraction coupling differs in these muscle cells from that now thought to be characteristic of striated muscle such as skeletal muscle and mammalian cardiac muscle. These structural dissimilarities also imply that the mechanism of relaxation in frog ventricular muscle differs from that considered typical of other striated muscles. Additional ultrastructural features of frog ventricular heart muscle include spherical electron-opaque bodies on thin filaments, inconstantly present, forming a rank across the I band about 150 mµ from the Z line, and membrane-bounded dense granules resembling neurosecretory granules. The functional significance of these features is not yet clear.

scholarly journals Disruption of the striated muscle glycogen-targeting subunit of protein phosphatase 1: influence of the genetic background

2007 ◽  
Vol 40 (2) ◽  
pp. 47-59 ◽  
Author(s):  
James Paterson ◽  
Ian R Kelsall ◽  
Patricia T W Cohen
Keyword(s):  
Skeletal Muscle ◽  
Glucose Transport ◽  
Muscle Glycogen ◽  
Protein Phosphatase ◽  
Striated Muscle ◽  
Protein Phosphatase 1 ◽  
Phosphorylase Kinase ◽  
Donor Strain ◽  
Key Factor

A prediabetic phenotype of glucose intolerance, insulin resistance and obesity was observed at ∼12 months of age in mice homozygous for a null allele of the major skeletal muscle glycogen-targeting subunit GM of protein phosphatase 1 (PP1) and derived from a 129/Ola donor strain. In this study, backcrossing of these mice (termed obese mice) onto two different genetic backgrounds gave rise to lean, glucose-tolerant, insulin-sensitive mice (termed lean mice), indicating that at least one variant gene in the 129/Ola background, not present in the C57BL/6 or 129s2/sV background, is required for the development of the prediabetic phenotype of obese mice. Slightly elevated AMP-activated protein kinase α2 activity in the skeletal muscle of lean C57BL/6 mice was also observed to a lesser extent in the obese mice. Normal or slightly raised in vivo glucose transport in lean C57BL/6 mice compared with decreased glucose transport in the obese mice supports the tenet that adequate transport of glucose may be a key factor in preventing the development of the prediabetic phenotype. The pH 6.8/pH 8.6 activity ratio of phosphorylase kinase was increased in lean C57BL/6 mice compared with controls indicating that phosphorylase kinase is an in vivo substrate of PP1-GM.

Models of contractile units and their assembly in smooth muscle

2005 ◽  
Vol 83 (10) ◽  
pp. 825-831 ◽  
Author(s):  
Farah Ali ◽  
Peter D Paré ◽  
Chun Y Seow
Keyword(s):  
Smooth Muscle ◽  
Striated Muscle ◽  
Dense Body ◽  
Unit Length ◽  
Muscle Length ◽  
Thick Filament ◽  
Contractile Apparatus ◽  
Thin Filaments ◽  
Dense Bodies ◽  
In Series

It is believed that the contractile filaments in smooth muscle are organized into arrays of contractile units (similar to the sarcomeric structure in striated muscle), and that such an organization is crucial for transforming the mechanical activities of actomyosin interaction into cell shortening and force generation. Details of the filament organization, however, are still poorly understood. Several models of contractile filament architecture are discussed here. To account for the linear relationship observed between the force generated by a smooth muscle and the muscle length at the plateau of an isotonic contraction, a model of contractile unit is proposed. The model consists of 2 dense bodies with actin (thin) filaments attached, and a myosin (thick) filament lying between the parallel thin filaments. In addition, the thick filament is assumed to span the whole contractile unit length, from dense body to dense body, so that when the contractile unit shortens, the amount of overlap between the thick and thin filaments (i.e., the distance between the dense bodies) decreases in exact proportion to the amount of shortening. Assembly of the contractile units into functional contractile apparatus is assumed to involve a group of cells that form a mechanical syncytium. The contractile apparatus is assumed malleable in that the number of contractile units in series and in parallel can be altered to accommodate strains on the muscle and to maintain the muscle's optimal mechanical function.Key words: contraction model, ultrastructure, length adaptation, plasticity.

scholarly journals Analysis of myofibrillar structure and assembly using fluorescently labeled contractile proteins.

1984 ◽  
Vol 98 (3) ◽  
pp. 825-833 ◽  
Author(s):  
J W Sanger ◽  
B Mittal ◽  
J M Sanger
Keyword(s):  
Actin Filaments ◽  
Striated Muscle ◽  
Contractile Proteins ◽  
Actin Binding ◽  
Thin Filaments ◽  
In Vitro System ◽  
Self Association ◽  
Cross Bridges

To study how contractile proteins become organized into sarcomeric units in striated muscle, we have exposed glycerinated myofibrils to fluorescently labeled actin, alpha-actinin, and tropomyosin. In this in vitro system, alpha-actinin bound to the Z-bands and the binding could not be saturated by prior addition of excess unlabeled alpha-actinin. Conditions known to prevent self-association of alpha-actinin, however, blocked the binding of fluorescently labeled alpha-actinin to Z-bands. When tropomyosin was removed from the myofibrils, alpha-actinin then added to the thin filaments as well as the Z-bands. Actin bound in a doublet pattern to the regions of the myosin filaments where there were free cross-bridges i.e., in that part of the A-band free of interdigitating native thin filaments but not in the center of the A-band which lacks cross-bridges. In the presence of 0.1-0.2 mM ATP, no actin binding occurred. When unlabeled alpha-actinin was added first to myofibrils and then labeled actin was added fluorescence occurred not in a doublet pattern but along the entire length of the myofibril. Tropomyosin did not bind to myofibrils unless the existing tropomyosin was first removed, in which case it added to the thin filaments in the l-band. Tropomyosin did bind, however, to the exogenously added tropomyosin-free actin that localizes as a doublet in the A-band. These results indicate that the alpha-actinin present in Z-bands of myofibrils is fully complexed with actin, but can bind exogenous alpha-actinin and, if actin is added subsequently, the exogenous alpha-actinin in the Z-band will bind the newly formed fluorescent actin filaments. Myofibrillar actin filaments did not increase in length when G-actin was present under polymerizing conditions, nor did they bind any added tropomyosin. These observations are discussed in terms of the structure and in vivo assembly of myofibrils.

scholarly journals Syncoilin is required for generating maximum isometric stress in skeletal muscle but dispensable for muscle cytoarchitecture

2008 ◽  
Vol 294 (5) ◽  
pp. C1175-C1182 ◽  
Author(s):  
Jianlin Zhang ◽  
Marie-Louise Bang ◽  
David S. Gokhin ◽  
Yingchun Lu ◽  
Li Cui ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Development ◽  
Striated Muscle ◽  
Neuromuscular Diseases ◽  
Eccentric Contraction ◽  
Lateral Force ◽  
Force Transmission ◽  
Skeletal Muscle Contraction ◽  
Supportive Role

Syncoilin is a striated muscle-specific intermediate filament-like protein, which is part of the dystrophin-associated protein complex (DPC) at the sarcolemma and provides a link between the extracellular matrix and the cytoskeleton through its interaction with α-dystrobrevin and desmin. Its upregulation in various neuromuscular diseases suggests that syncoilin may play a role in human myopathies. To study the functional role of syncoilin in cardiac and skeletal muscle in vivo, we generated syncoilin-deficient ( syncoilin−/−) mice. Our detailed analysis of these mice up to 2 yr of age revealed that syncoilin is entirely dispensable for cardiac and skeletal muscle development and maintenance of cellular structure but is required for efficient lateral force transmission during skeletal muscle contraction. Notably, syncoilin−/− skeletal muscle generates less maximal isometric stress than wild-type (WT) muscle but is as equally susceptible to eccentric contraction-induced injury as WT muscle. This suggests that syncoilin may play a supportive role for desmin in the efficient coupling of mechanical stress between the myofibril and fiber exterior. It is possible that the reduction in isometric stress production may predispose the syncoilin skeletal muscle to a dystrophic condition.

scholarly journals Relaxed tarantula skeletal muscle has two ATP energy-saving mechanisms

2021 ◽  
Vol 153 (3) ◽  
Author(s):  
Weikang Ma ◽  
Sebastian Duno-Miranda ◽  
Thomas Irving ◽  
Roger Craig ◽  
Raúl Padrón
Keyword(s):  
Skeletal Muscle ◽  
Energy Saving ◽  
Striated Muscle ◽  
Mammalian Skeletal Muscle ◽  
X Ray Diffraction ◽  
Thin Filaments ◽  
Thick Filaments ◽  
Refractory State ◽  
Increasing Temperature ◽  
Induced Changes

Myosin molecules in the relaxed thick filaments of striated muscle have a helical arrangement in which the heads of each molecule interact with each other, forming the interacting-heads motif (IHM). In relaxed mammalian skeletal muscle, this helical ordering occurs only at temperatures &gt;20°C and is disrupted when temperature is decreased. Recent x-ray diffraction studies of live tarantula skeletal muscle have suggested that the two myosin heads of the IHM (blocked heads [BHs] and free heads [FHs]) have very different roles and dynamics during contraction. Here, we explore temperature-induced changes in the BHs and FHs in relaxed tarantula skeletal muscle. We find a change with decreasing temperature that is similar to that in mammals, while increasing temperature induces a different behavior in the heads. At 22.5°C, the BHs and FHs containing ADP.Pi are fully helically organized, but they become progressively disordered as temperature is lowered or raised. Our interpretation suggests that at low temperature, while the BHs remain ordered the FHs become disordered due to transition of the heads to a straight conformation containing Mg.ATP. Above 27.5°C, the nucleotide remains as ADP.Pi, but while BHs remain ordered, half of the FHs become progressively disordered, released semipermanently at a midway distance to the thin filaments while the remaining FHs are docked as swaying heads. We propose a thermosensing mechanism for tarantula skeletal muscle to explain these changes. Our results suggest that tarantula skeletal muscle thick filaments, in addition to having a superrelaxation–based ATP energy-saving mechanism in the range of 8.5–40°C, also exhibit energy saving at lower temperatures (&lt;22.5°C), similar to the proposed refractory state in mammals.

scholarly journals Troponin Variants as Markers of Skeletal Muscle Health and Diseases

2021 ◽  
Vol 12 ◽  
Author(s):  
Monica Rasmussen ◽  
Jian-Ping Jin
Keyword(s):  
Skeletal Muscle ◽  
Troponin I ◽  
Striated Muscle ◽  
Troponin T ◽  
Muscle Quality ◽  
Striated Muscles ◽  
Thin Filaments ◽  
Age Related ◽  
Development And Aging ◽  
Regulation Of Muscle Contraction

Ca2+-regulated contractility is a key determinant of the quality of muscles. The sarcomeric myofilament proteins are essential players in the contraction of striated muscles. The troponin complex in the actin thin filaments plays a central role in the Ca2+-regulation of muscle contraction and relaxation. Among the three subunits of troponin, the Ca2+-binding subunit troponin C (TnC) is a member of the calmodulin super family whereas troponin I (TnI, the inhibitory subunit) and troponin T (TnT, the tropomyosin-binding and thin filament anchoring subunit) are striated muscle-specific regulatory proteins. Muscle type-specific isoforms of troponin subunits are expressed in fast and slow twitch fibers and are regulated during development and aging, and in adaptation to exercise or disuse. TnT also evolved with various alternative splice forms as an added capacity of muscle functional diversity. Mutations of troponin subunits cause myopathies. Owing to their physiological and pathological importance, troponin variants can be used as specific markers to define muscle quality. In this focused review, we will explore the use of troponin variants as markers for the fiber contents, developmental and differentiation states, contractile functions, and physiological or pathophysiological adaptations of skeletal muscle. As protein structure defines function, profile of troponin variants illustrates how changes at the myofilament level confer functional qualities at the fiber level. Moreover, understanding of the role of troponin modifications and mutants in determining muscle contractility in age-related decline of muscle function and in myopathies informs an approach to improve human health.

Exercise promotes a subcellular redistribution of calcium-stimulated protease activity in striated muscle

1999 ◽  
Vol 77 (1) ◽  
pp. 42-47 ◽  
Author(s):  
Gavin D Arthur ◽  
Timothy S Booker ◽  
Angelo N Belcastro
Keyword(s):  
Skeletal Muscle ◽  
Cardiac Muscle ◽  
Protease Activity ◽  
Striated Muscle ◽  
Contractile Activity ◽  
Particulate Fraction ◽  
Dependent Manner ◽  
Calcium Dependent ◽  
Study Support

The aims of this study were (i) to investigate whether the contractile activity associated with running increases calcium-stimulated, calpastatin-inhibited protease activity (calpain-like) in a time-dependent manner and (ii) to determine whether the changes, if any, are proportionately distributed between soluble (cytosolic) and particulate (bound) fractions of striated muscle in vivo. Calcium-dependent, calpastatin-inhibited caseinolysis (i.e., calpain-like activity) was measured in control and exercised rats (25 m/min, 0% grade) at 2, 5, 15, 30, and 60 min. Total calpain-like activity in skeletal muscle increased by 26% (13.2 ± 1.3 vs. 17.9 ± 2.2 U/g wet wt.) (p < 0.05) after running (60 min), accompanied by an increased activity in the particulate fraction. In cardiac muscle, exercise (60 min) increased total calpain-like activity by 33% (p < 0.05), which was attributable to increases in both the cytosolic and particulate fractions. Both tissues responded with an early (2-5 min) activation of total calpain-like activity (p < 0.05), supported by early increases for particulate fractions from skeletal muscle; whereas for cardiac muscle, a noticeable early drop (p < 0.05) occurred in the particulate fraction. Minimal changes were observed for total, cytosolic, and particulate fractions of noncontracting tissue (i.e., liver). The results of this study support the hypothesis that the total calpain-like activity increases associated with level running occur early on with exercise and that the increases are accompanied by changes in the redistribution of soluble to particulate fractions. The changes would set the stage for enhanced rates of protein degradation known to occur in striated muscle with exercise.Key words: nonlysosomal proteases, calcium-dependent proteolysis, muscle damage.

scholarly journals Extracellular Vesicles From Adipose Stem Cells Prevent Muscle Damage and Inflammation in a Mouse Model of Hind Limb Ischemia

2020 ◽  
Vol 40 (1) ◽  
pp. 239-254 ◽  
Author(s):  
Federico Figliolini ◽  
Andrea Ranghino ◽  
Cristina Grange ◽  
Massimo Cedrino ◽  
Marta Tapparo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mouse Model ◽  
Muscle Damage ◽  
Extracellular Vesicles ◽  
Muscle Regeneration ◽  
Hindlimb Ischemia ◽  
Vascular Growth ◽  
Muscle Protection

Objectives: Critical hindlimb ischemia is a severe consequence of peripheral artery disease. Surgical treatment does not prevent skeletal muscle impairment or improve long-term patient outcomes. The present study investigates the protective/regenerative potential and the mechanism of action of adipose stem cell-derived extracellular vesicles (ASC-EVs) in a mouse model of hindlimb ischemia. Approach and Results: We demonstrated that ASC-EVs exert a protective effect on muscle damage by acting both on tissue microvessels and muscle cells. The genes involved in muscle regeneration were up-regulated in the ischemic muscles of ASC-EV-treated animals. MyoD expression has also been confirmed in satellite cells. This was followed by a reduction in muscle function impairment in vivo. ASC-EVs drive myoblast proliferation and differentiation in the in vitro ischemia/reoxygenation model. Moreover, ASC-EVs have shown an anti-apoptotic effect both in vitro and in vivo. Transcriptomic analyses have revealed that ASC-EVs carry a variety of pro-angiogenic mRNAs, while proteomic analyses have demonstrated an enrichment of NRG1 (neuregulin 1). A NRG1 blocking antibody used in vivo demonstrated that NRG1 is relevant to ASC-EV-induced muscle protection, vascular growth, and recruitment of inflammatory cells. Finally, bioinformatic analyses on 18 molecules that were commonly detected in ASC-EVs, including mRNAs and proteins, confirmed the enrichment of pathways involved in vascular growth and muscle regeneration/protection. Conclusions: This study demonstrates that ASC-EVs display pro-angiogenic and skeletal muscle protective properties that are associated with their NRG1/mRNA cargo. We, therefore, propose that ASC-EVs are a useful tool for therapeutic angiogenesis and muscle protection.

Sign in / Sign up

Export Citation Format

Share Document