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 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.

scholarly journals Ca2+ Regulation of Rabbit Skeletal Muscle Thin Filament Sliding: Role of Cross-Bridge Number

2003 ◽  
Vol 85 (3) ◽  
pp. 1775-1786 ◽  
Author(s):  
Bo Liang ◽  
Ying Chen ◽  
Chien-Kao Wang ◽  
Zhaoxiong Luo ◽  
Michael Regnier ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Thin Filament ◽  
Rabbit Skeletal Muscle ◽  
Cross Bridge ◽  
Muscle Thin Filament ◽  
Bridge Number

scholarly journals The Role of Thin Filament Calcium Sensitivity in Modulating Relaxation Time of Soleus and EDL Skeletal Muscle

2020 ◽  
Vol 118 (3) ◽  
pp. 122a
Author(s):  
Connor Tyree ◽  
Kyra Peczkowski ◽  
Paul M. Janssen ◽  
Jill Rafael-Fortney ◽  
Jonathan P. Davis
Keyword(s):  
Skeletal Muscle ◽  
Relaxation Time ◽  
Thin Filament ◽  
Calcium Sensitivity

scholarly journals Role of Actin C-Terminus in Regulation of Striated Muscle Thin Filament

2008 ◽  
Vol 94 (4) ◽  
pp. 1341-1347 ◽  
Author(s):  
Masłgorzata Śliwińska ◽  
Radosław Skórzewski ◽  
Joanna Moraczewska
Keyword(s):  
Thin Filament ◽  
Striated Muscle ◽  
C Terminus ◽  
Muscle Thin Filament

scholarly journals Role of the HPRG Component of Striated Muscle AMP Deaminase in the Stability and Cellular Behaviour of the Enzyme

Biomolecules ◽  
2018 ◽  
Vol 8 (3) ◽  
pp. 79
Author(s):  
Francesca Ronca ◽  
Antonio Raggi
Keyword(s):  
Metal Binding ◽  
Thin Filament ◽  
Striated Muscle ◽  
Binding Motif ◽  
Amp Deaminase ◽  
Binding Properties ◽  
Preferential Localization ◽  
The Stability ◽  
Cellular Behaviour

Multiple muscle-specific isoforms of the Zn2+ metalloenzyme AMP deaminase (AMPD) have been identified based on their biochemical and genetic differences. Our previous observations suggested that the metal binding protein histidine-proline-rich glycoprotein (HPRG) participates in the assembly and maintenance of skeletal muscle AMP deaminase (AMPD1) by acting as a zinc chaperone. The evidence of a role of millimolar-strength phosphate in stabilizing the AMPD-HPRG complex of both AMPD1 and cardiac AMP deaminase (AMPD3) is suggestive of a physiological mutual dependence between the two subunit components with regard to the stability of the two isoforms of striated muscle AMPD. The observed influence of the HPRG content on the catalytic behavior of the two enzymes further strengthens this hypothesis. Based on the preferential localization of HPRG at the sarcomeric I-band and on the presence of a Zn2+ binding motif in the N-terminal regions of fast TnT and of the AMPD1 catalytic subunit, we advance the hypothesis that the Zn binding properties of HPRG could promote the association of AMPD1 to the thin filament.

scholarly journals Neurohypophyseal hormones and skeletal muscle: a tale of two faces

2020 ◽  
Vol 30 (1) ◽  
pp. 53-57
Author(s):  
Alexandra Benoni ◽  
Alessandra Renzini ◽  
Giorgia Cavioli ◽  
Sergio Adamo
Keyword(s):  
Skeletal Muscle ◽  
Muscle Atrophy ◽  
Cancer Cachexia ◽  
Muscle Wasting ◽  
Striated Muscle ◽  
Cardiac Atrophy ◽  
Neurohypophyseal Hormones

The neurohypophyseal hormones vasopressin and oxytocin were invested, in recent years, with novel functions upon striated muscle, regulating its differentiation, trophism, and homeostasis. Recent studies highlight that these hormones not only target skeletal muscle but represent novel myokines. We discuss the possibility of exploiting the muscle hypertrophying activity of oxytocin to revert muscle atrophy, including cancer cachexia muscle wasting. Furthermore, the role of oxytocin in cardiac homeostasis and the possible role of cardiac atrophy as a concause of death in cachectic patients is discussed.

scholarly journals Dysregulation of NRAP degradation by KLHL41 contributes to pathophysiology in nemaline myopathy

2019 ◽  
Vol 28 (15) ◽  
pp. 2549-2560 ◽  
Author(s):  
Caroline Jirka ◽  
Jasmine H Pak ◽  
Claire A Grosgogeat ◽  
Michael Mario Marchetii ◽  
Vandana A Gupta
Keyword(s):  
Skeletal Muscle ◽  
Thin Filament ◽  
Muscle Development ◽  
Nemaline Myopathy ◽  
Therapeutic Interventions ◽  
Transgenic Zebrafish ◽  
Anchoring Protein ◽  
And Function

Abstract Nemaline myopathy (NM) is the most common form of congenital myopathy that results in hypotonia and muscle weakness. This disease is clinically and genetically heterogeneous, but three recently discovered genes in NM encode for members of the Kelch family of proteins. Kelch proteins act as substrate-specific adaptors for Cullin 3 (CUL3) E3 ubiquitin ligase to regulate protein turnover through the ubiquitin-proteasome machinery. Defects in thin filament formation and/or stability are key molecular processes that underlie the disease pathology in NM; however, the role of Kelch proteins in these processes in normal and diseases conditions remains elusive. Here, we describe a role of NM causing Kelch protein, KLHL41, in premyofibil-myofibil transition during skeletal muscle development through a regulation of the thin filament chaperone, nebulin-related anchoring protein (NRAP). KLHL41 binds to the thin filament chaperone NRAP and promotes ubiquitination and subsequent degradation of NRAP, a process that is critical for the formation of mature myofibrils. KLHL41 deficiency results in abnormal accumulation of NRAP in muscle cells. NRAP overexpression in transgenic zebrafish resulted in a severe myopathic phenotype and absence of mature myofibrils demonstrating a role in disease pathology. Reducing Nrap levels in KLHL41 deficient zebrafish rescues the structural and function defects associated with disease pathology. We conclude that defects in KLHL41-mediated ubiquitination of sarcomeric proteins contribute to structural and functional deficits in skeletal muscle. These findings further our understanding of how the sarcomere assembly is regulated by disease-causing factors in vivo, which will be imperative for developing mechanism-based specific therapeutic interventions.

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