scholarly journals Tropomodulin isoforms regulate thin filament pointed-end capping and skeletal muscle physiology

2010 ◽  
Vol 189 (1) ◽  
pp. 95-109 ◽  
Author(s):  
David S. Gokhin ◽  
Raymond A. Lewis ◽  
Caroline R. McKeown ◽  
Roberta B. Nowak ◽  
Nancy E. Kim ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Thin Filament ◽  
Striated Muscle ◽  
Fiber Type ◽  
Actin Dynamics ◽  
Muscle Physiology ◽  
Skeletal Muscle Function ◽  
Capping Proteins ◽  
Locomotor Deficits ◽  
End Capping

During myofibril assembly, thin filament lengths are precisely specified to optimize skeletal muscle function. Tropomodulins (Tmods) are capping proteins that specify thin filament lengths by controlling actin dynamics at pointed ends. In this study, we use a genetic targeting approach to explore the effects of deleting Tmod1 from skeletal muscle. Myofibril assembly, skeletal muscle structure, and thin filament lengths are normal in the absence of Tmod1. Tmod4 localizes to thin filament pointed ends in Tmod1-null embryonic muscle, whereas both Tmod3 and -4 localize to pointed ends in Tmod1-null adult muscle. Substitution by Tmod3 and -4 occurs despite their weaker interactions with striated muscle tropomyosins. However, the absence of Tmod1 results in depressed isometric stress production during muscle contraction, systemic locomotor deficits, and a shift to a faster fiber type distribution. Thus, Tmod3 and -4 compensate for the absence of Tmod1 structurally but not functionally. We conclude that Tmod1 is a novel regulator of skeletal muscle physiology.

Tropomodulin isoforms regulate thin filament pointed-end capping and skeletal muscle physiology

2010 ◽  
Vol 135 (5) ◽  
pp. i4-i4
Author(s):  
David S. Gokhin ◽  
Raymond A. Lewis ◽  
Caroline R. McKeown ◽  
Roberta B. Nowak ◽  
Nancy E. Kim ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Thin Filament ◽  
Muscle Physiology ◽  
End Capping ◽  
Pointed End

scholarly journals Thin filaments elongate from their pointed ends during myofibril assembly in Drosophila indirect flight muscle

2001 ◽  
Vol 155 (6) ◽  
pp. 1043-1054 ◽  
Author(s):  
Michelle Mardahl-Dumesnil ◽  
Velia M. Fowler
Keyword(s):  
Thin Filament ◽  
Muscle Development ◽  
Striated Muscle ◽  
Flight Muscle ◽  
De Novo ◽  
Indirect Flight Muscle ◽  
Actin Dynamics ◽  
Thin Filaments ◽  
End Capping ◽  
Pointed End

Tropomodulin (Tmod) is an actin pointed-end capping protein that regulates actin dynamics at thin filament pointed ends in striated muscle. Although pointed-end capping by Tmod controls thin filament lengths in assembled myofibrils, its role in length specification during de novo myofibril assembly is not established. We used the Drosophila Tmod homologue, sanpodo (spdo), to investigate Tmod's function during muscle development in the indirect flight muscle. SPDO was associated with the pointed ends of elongating thin filaments throughout myofibril assembly. Transient overexpression of SPDO during myofibril assembly irreversibly arrested elongation of preexisting thin filaments. However, the lengths of thin filaments assembled after SPDO levels had declined were normal. Flies with a preponderance of abnormally short thin filaments were unable to fly. We conclude that: (a) thin filaments elongate from their pointed ends during myofibril assembly; (b) pointed ends are dynamically capped at endogenous levels of SPDO so as to allow elongation; (c) a transient increase in SPDO levels during myofibril assembly converts SPDO from a dynamic to a permanent cap; and (d) developmental regulation of pointed-end capping during myofibril assembly is crucial for specification of final thin filament lengths, myofibril structure, and muscle function.

scholarly journals ProNGF/p75NTR Axis Drives Fiber Type Specification by Inducing the Fast-Glycolytic Phenotype in Mouse Skeletal Muscle Cells

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2232
Author(s):  
Valentina Pallottini ◽  
Mayra Colardo ◽  
Claudia Tonini ◽  
Noemi Martella ◽  
Georgios Strimpakos ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Myogenic Differentiation ◽  
Fiber Type ◽  
Pcr Analysis ◽  
Mdx Mouse ◽  
Mdx Mice ◽  
Muscle Physiology

Despite its undisputable role in the homeostatic regulation of the nervous system, the nerve growth factor (NGF) also governs the relevant cellular processes in other tissues and organs. In this study, we aimed at assessing the expression and the putative involvement of NGF signaling in skeletal muscle physiology. To reach this objective, we employed satellite cell-derived myoblasts as an in vitro culture model. In vivo experiments were performed on Tibialis anterior from wild-type mice and an mdx mouse model of Duchenne muscular dystrophy. Targets of interest were mainly assessed by means of morphological, Western blot and qRT-PCR analysis. The results show that proNGF is involved in myogenic differentiation. Importantly, the proNGF/p75NTR pathway orchestrates a slow-to-fast fiber type transition by counteracting the expression of slow myosin heavy chain and that of oxidative markers. Concurrently, proNGF/p75NTR activation facilitates the induction of fast myosin heavy chain and of fast/glycolytic markers. Furthermore, we also provided evidence that the oxidative metabolism is impaired in mdx mice, and that these alterations are paralleled by a prominent buildup of proNGF and p75NTR. These findings underline that the proNGF/p75NTR pathway may play a crucial role in fiber type determination and suggest its prospective modulation as an innovative therapeutic approach to counteract muscle disorders.

scholarly journals Transcriptome features of striated muscle aging and predictability of protein level changes

2021 ◽  
Author(s):  
Yu Han ◽  
Lauren Z. Li ◽  
Nikhitha L. Kastury ◽  
Cody T. Thomas ◽  
Maggie P. Y. Lam ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Level ◽  
Striated Muscle ◽  
Muscle Physiology ◽  
Sequencing Data ◽  
Individual Gene ◽  
Protein Levels ◽  
Muscle Aging ◽  
Age Dependent ◽  
Transcriptomic Changes

RNA and protein levels correlate only partially and some transcripts are better correlated with their protein counterparts than others. This suggests that in aging and disease studies, some transcriptomics markers may carry more information in predicting protein-level changes. Here we applied a computational data analysis workflow to predict which transcriptomic changes are more likely relevant to protein-level regulation in striated muscle aging. The protein predictability of each transcript is estimated from existing large proteogenomics data sets, then transferred to new total RNA sequencing data comparing skeletal muscle and cardiac muscle in young adult (~4 months) mice vs. early aging (~20 months) mice. Aging cardiac and skeletal muscles both invoke transcriptomic changes in innate immune system and mitochondria pathways but diverge in extracellular matrix processes. On an individual gene level, we identified 611 age-associated signatures in skeletal and cardiac muscles at 10% FDR, including a number of myokine and cardiokine encoding genes. We estimate that about 48% of the aging-associated transcripts may predict protein levels well (r ≥ 0.5). In parallel, a comparison of the identified aging-regulated genes with public human transcriptomics data showed that only 35-45% of the identified genes show an age-dependent expression in corresponding human tissues. Finally, integrating both protein predictability and human translatability from multiple data sources, we nominate 134 prioritized aging signatures that are predicted to correlate strongly with protein levels and that show age-dependent expression in humans. These prioritized gene signatures may hold promise to understanding heart and skeletal muscle physiology in human and mouse aging.

scholarly journals Skeletal muscle function and water permeability in aquaporin-4 deficient mice

2000 ◽  
Vol 278 (6) ◽  
pp. C1108-C1115 ◽  
Author(s):  
Baoxue Yang ◽  
Jean-Marc Verbavatz ◽  
Yuanlin Song ◽  
L. Vetrivel ◽  
Geoffrey Manley ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Water Permeability ◽  
Muscle Function ◽  
Force Generation ◽  
Muscle Physiology ◽  
Wild Type ◽  
Volume Changes ◽  
Skeletal Muscle Function ◽  
Performance Time ◽  
Aqp4 Protein

It has been proposed that aquaporin-4 (AQP4), a water channel expressed at the plasmalemma of skeletal muscle cells, is important in normal muscle physiology and in the pathophysiology of Duchenne's muscular dystrophy. To test this hypothesis, muscle water permeability and function were compared in wild-type and AQP4 knockout mice. Immunofluorescence and freeze-fracture electron microscopy showed AQP4 protein expression in plasmalemma of fast-twitch skeletal muscle fibers of wild-type mice. Osmotic water permeability was measured in microdissected muscle fibers from the extensor digitorum longus (EDL) and fractionated membrane vesicles from EDL homogenates. With the use of spatial-filtering microscopy to measure osmotically induced volume changes in EDL fibers, half times ( t 1/2) for osmotic equilibration (7.5–8.5 s) were not affected by AQP4 deletion. Stopped-flow light-scattering measurements of osmotically induced volume changes in plasmalemma vesicles also showed no significant differences in water permeability. Similar water permeability, yet ∼90% decreased AQP4 protein expression was found in EDL from mdx mice that lack dystrophin. Skeletal muscle function was measured by force generation in isolated EDL, treadmill performance time, and in vivo muscle swelling in response to water intoxication. No differences were found in EDL force generation after electrical stimulation [42 ± 2 (wild-type) vs. 41 ± 2 (knockout) g/s], treadmill performance time (22 vs. 26 min; 29 m/min, 13° incline), or muscle swelling (2.8 vs. 2.9% increased water content at 90 min after intraperitoneal water infusion). Together these results provide evidence against a significant role of AQP4 in skeletal muscle physiology in mice.

scholarly journals The Role of Z-disc Proteins in Myopathy and Cardiomyopathy

2021 ◽  
Vol 22 (6) ◽  
pp. 3058
Author(s):  
Kirsty Wadmore ◽  
Amar J. Azad ◽  
Katja Gehmlich
Keyword(s):  
Skeletal Muscle ◽  
Thin Filament ◽  
Striated Muscle ◽  
Normal Population ◽  
Pathogenic Variants ◽  
Variant Frequency ◽  
Alternatively Spliced ◽  
Protein Rich ◽  
Six Genes

The Z-disc acts as a protein-rich structure to tether thin filament in the contractile units, the sarcomeres, of striated muscle cells. Proteins found in the Z-disc are integral for maintaining the architecture of the sarcomere. They also enable it to function as a (bio-mechanical) signalling hub. Numerous proteins interact in the Z-disc to facilitate force transduction and intracellular signalling in both cardiac and skeletal muscle. This review will focus on six key Z-disc proteins: α-actinin 2, filamin C, myopalladin, myotilin, telethonin and Z-disc alternatively spliced PDZ-motif (ZASP), which have all been linked to myopathies and cardiomyopathies. We will summarise pathogenic variants identified in the six genes coding for these proteins and look at their involvement in myopathy and cardiomyopathy. Listing the Minor Allele Frequency (MAF) of these variants in the Genome Aggregation Database (GnomAD) version 3.1 will help to critically re-evaluate pathogenicity based on variant frequency in normal population cohorts.

scholarly journals Localization of dystrophin gene transcripts during mouse embryogenesis.

1992 ◽  
Vol 119 (4) ◽  
pp. 811-821 ◽  
Author(s):  
D Houzelstein ◽  
G E Lyons ◽  
J Chamberlain ◽  
M E Buckingham
Keyword(s):  
Skeletal Muscle ◽  
Striated Muscle ◽  
Fiber Type ◽  
Endocrine System ◽  
Dystrophin Gene ◽  
Mouse Embryogenesis ◽  
Tissue Sections ◽  
Gene Transcripts ◽  
High Level

The spatial and temporal expression of the dystrophin gene has been examined during mouse embryogenesis, using in situ hybridization on tissue sections with a probe from the 5' end of the dystrophin coding sequence. In striated muscle, dystrophin transcripts are detectable from about 9 d in the heart and slightly later in skeletal muscle. However, there is an important difference between the two types of muscle: the heart is already functional as a contractile organ before the appearance of dystrophin transcripts, whereas this is not the case in skeletal muscle, where dystrophin and myosin heavy chain transcripts are first detectable at the same time. In the heart, dystrophin transcripts accumulate initially in the outflow tract and, at later stages, in both the atria and ventricles. In skeletal muscle, the gene is expressed in all myocytes irrespective of fiber type. In smooth muscle dystrophin transcripts are first detectable from 11 d post coitum in blood vessels, and subsequently in lung bronchi and in the digestive tract. The other major tissue where the dystrophin gene is expressed is the brain, where transcripts are clearly detectable in the cerebellum from 13 d. High-level expression of the gene is also seen in particular regions of the forebrain involved in the regulation of circadian rhythms, the endocrine system, and olfactory function, not previously identified in this context. The findings are discussed in the context of the pathology of Duchenne muscular dystrophy.

Muscle Bioenergetic Considerations for Intrinsic Laryngeal Skeletal Muscle Physiology

2017 ◽  
Vol 60 (5) ◽  
pp. 1254-1263 ◽  
Author(s):  
Mary J. Sandage ◽  
Audrey G. Smith
Keyword(s):  
Skeletal Muscle ◽  
Exercise Physiology ◽  
Muscle Metabolism ◽  
Theoretical Models ◽  
Muscle Physiology ◽  
Voice Training ◽  
Exercise Science ◽  
Skeletal Muscle Function ◽  
Human Models ◽  
Intrinsic Laryngeal Muscle

PurposeIntrinsic laryngeal skeletal muscle bioenergetics, the means by which muscles produce fuel for muscle metabolism, is an understudied aspect of laryngeal physiology with direct implications for voice habilitation and rehabilitation. The purpose of this review is to describe bioenergetic pathways identified in limb skeletal muscle and introduce bioenergetic physiology as a necessary parameter for theoretical models of laryngeal skeletal muscle function.MethodA comprehensive review of the human intrinsic laryngeal skeletal muscle physiology literature was conducted. Findings regarding intrinsic laryngeal muscle fiber complement and muscle metabolism in human models are summarized and exercise physiology methodology is applied to identify probable bioenergetic pathways used for voice function.ResultsIntrinsic laryngeal skeletal muscle fibers described in human models support the fast, high-intensity physiological requirements of these muscles for biological functions of airway protection. Inclusion of muscle bioenergetic constructs in theoretical modeling of voice training, detraining, fatigue, and voice loading have been limited.ConclusionsMuscle bioenergetics, a key component for muscle training, detraining, and fatigue models in exercise science, is a little-considered aspect of intrinsic laryngeal skeletal muscle physiology. Partnered with knowledge of occupation-specific voice requirements, application of bioenergetics may inform novel considerations for voice habilitation and rehabilitation.

Effects of streptozotocin-induced diabetes and physical training on gene expression of titin-based stretch-sensing complexes in mouse striated muscle

2007 ◽  
Vol 292 (2) ◽  
pp. E533-E542 ◽  
Author(s):  
T. Maarit Lehti ◽  
Mika Silvennoinen ◽  
Riikka Kivelä ◽  
Heikki Kainulainen ◽  
Jyrki Komulainen
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Cardiac Muscle ◽  
Physical Training ◽  
Striated Muscle ◽  
Fiber Type ◽  
Training Session ◽  
Mrna Levels ◽  
Strain Sensing ◽  
Induced Changes

In striated muscle, a sarcomeric noncontractile protein, titin, is proposed to form the backbone of the stress- and strain-sensing structures. We investigated the effects of diabetes, physical training, and their combination on the gene expression of proteins of putative titin stretch-sensing complexes in skeletal and cardiac muscle. Mice were divided into control (C), training (T), streptozotocin-induced diabetic (D), and diabetic training (DT) groups. Training groups performed for 1, 3, or 5 wk of endurance training on a motor-driven treadmill. Muscle samples from T and DT groups together with respective controls were collected 24 h after the last training session. Gene expression of calf muscles (soleus, gastrocnemius, and plantaris) and cardiac muscle were analyzed using microarray and quantitative PCR. Diabetes induced changes in mRNA expression of the proteins of titin stretch-sensing complexes in Z-disc (MLP, myostatin), I-band (CARP, Ankrd2), and M-line (titin kinase signaling). Training alleviated diabetes-induced changes in most affected mRNA levels in skeletal muscle but only one change in cardiac muscle. In conclusion, we showed diabetes-induced changes in mRNA levels of several fiber-type-biased proteins (MLP, myostatin, Ankrd2) in skeletal muscle. These results are consistent with previous observations of diabetes-induced atrophy leading to slower fiber type composition. The ability of exercise to alleviate diabetes-induced changes may indicate slower transition of fiber type.

scholarly journals Working around the clock: circadian rhythms and skeletal muscle

2009 ◽  
Vol 107 (5) ◽  
pp. 1647-1654 ◽  
Author(s):  
Xiping Zhang ◽  
Thomas J. Dube ◽  
Karyn A. Esser
Keyword(s):  
Skeletal Muscle ◽  
Molecular Clock ◽  
Time Of Day ◽  
Muscle Disease ◽  
Muscle Physiology ◽  
Skeletal Muscle Function ◽  
Temporal Specificity ◽  
Muscle Research ◽  
Normal Expression ◽  
Normal Metabolism

The study of the circadian molecular clock in skeletal muscle is in the very early stages. Initial research has demonstrated the presence of the molecular clock in skeletal muscle and that skeletal muscle of a clock-compromised mouse, Clock mutant, exhibits significant disruption in normal expression of many genes required for adult muscle structure and metabolism. In light of the growing association between the molecular clock, metabolism, and metabolic disease, it will also be important to understand the contribution of circadian factors to normal metabolism, metabolic responses to muscle training, and contribution of the molecular clock in muscle-to-muscle disease (e.g., insulin resistance). Consistent with the potential for the skeletal muscle molecular clock modulating skeletal muscle physiology, there are findings in the literature that there is significant time-of-day effects for strength and metabolism. Additionally, there is some recent evidence that temporal specificity is important for optimizing training for muscular performance. While these studies do not prove that the molecular clock in skeletal muscle is important, they are suggestive of a circadian contribution to skeletal muscle function. The application of well-established models of skeletal muscle research in function and metabolism with available genetic models of molecular clock disruption will allow for more mechanistic understanding of potential relationships.

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