Actin-Accumulation Myopathy

Last update 01 Nov 2024

Basic Info

Synonyms

Actin Filament Aggregate Myopathy, Actin Myopathy, Actin accumulation myopathy

+ [20]

Introduction

An inherited myopathy caused by mutations in the ACTA1 gene, encoding actin, alpha skeletal muscle. The phenotype is highly variable, and as such attempts at classification by clinical features is not optimal. Generally, affected individuals have generalized muscle weakness, typically involving proximal muscles, the face, bulbar and respiratory muscles.

100 Clinical Results associated with Actin-Accumulation Myopathy

100 Translational Medicine associated with Actin-Accumulation Myopathy

0 Patents (Medical) associated with Actin-Accumulation Myopathy

Literatures (Medical) associated with Actin-Accumulation Myopathy

27 May 2024·JACS Au

Visualizing Actin Packing and the Effects of Actin Attachment on Lipid Membrane Viscosity Using Molecular Rotors

Article

Author: Brooks, Nickolas J ; Kuimova, Marina K ; Ioannou, Ion A ; Elani, Yuval

The actin cytoskeleton and its elaborate interplay with the plasma membrane participate in and control numerous biological processes in eukaryotic cells. Malfunction of actin networks and changes in their dynamics are related to various diseases, from actin myopathies to uncontrolled cell growth and tumorigenesis. Importantly, the biophysical and mechanical properties of actin and its assemblies are deeply intertwined with the biological functions of the cytoskeleton. Novel tools to study actin and its associated biophysical features are, therefore, of prime importance. Here we develop a new approach which exploits fluorescence lifetime imaging microscopy (FLIM) and environmentally sensitive fluorophores termed molecular rotors, acting as quantitative microviscosity sensors, to monitor dynamic viscoelastic properties of both actin structures and lipid membranes. In order to reproduce a minimal actin cortex in synthetic cell models, we encapsulated and attached actin networks to the lipid bilayer of giant unilamellar vesicles (GUVs). Using a cyanine-based molecular rotor, DiSC₂(3), we show that different types of actin bundles are characterized by distinct packing, which can be spatially resolved using FLIM. Similarly, we show that a lipid bilayer-localized molecular rotor can monitor the effects of attaching cross-linked actin networks to the lipid membrane, revealing an increase in membrane viscosity upon actin attachment. Our approach bypasses constraints associated with existing methods for actin imaging, many of which lack the capability for direct visualization of biophysical properties. It can therefore contribute to a deeper understanding of the role that actin plays in fundamental biological processes and help elucidate the underlying biophysics of actin-related diseases.

01 Apr 2024·Journal of General Physiology

Tirasemtiv enhances submaximal muscle tension in an Acta1:p.Asp286Gly mouse model of nemaline myopathy

Article

Author: Rossi, Maira ; Pellegrino, Maria-Antonietta ; Galli, Ricardo A ; Borsboom, Tamara C ; Gondin, Julien ; Gineste, Charlotte ; Bottinelli, Roberto ; Brocca, Lorenza ; Hwee, Darren T ; Malik, Fady I ; de Winter, Josine M ; Ottenheijm, Coen A C

Nemaline myopathies are the most common form of congenital myopathies. Variants in ACTA1 (NEM3) comprise 15–25% of all nemaline myopathy cases. Patients harboring variants in ACTA1 present with a heterogeneous disease course characterized by stable or progressive muscle weakness and, in severe cases, respiratory failure and death. To date, no specific treatments are available. Since NEM3 is an actin-based thin filament disease, we tested the ability of tirasemtiv, a fast skeletal muscle troponin activator, to improve skeletal muscle function in a mouse model of NEM3, harboring the patient-based p.Asp286Gly variant in Acta1. Acute and long-term tirasemtiv treatment significantly increased muscle contractile capacity at submaximal stimulation frequencies in both fast-twitch extensor digitorum longus and gastrocnemius muscle, and intermediate-twitch diaphragm muscle in vitro and in vivo. Additionally, long-term tirasemtiv treatment in NEM3 mice resulted in a decreased respiratory rate with preserved minute volume, suggesting more efficient respiration. Altogether, our data support the therapeutic potential of fast skeletal muscle troponin activators in alleviating skeletal muscle weakness in a mouse model of NEM3 caused by the Acta1:p.Asp286Gly variant.

01 Sep 2022·Cytoskeleton

Comparison of incorporation of wild type and mutated actins into sarcomeres in skeletal muscle cells: A fluorescence recovery after photobleaching study

Article

Author: Mittal, Balraj ; Fan, Yingli ; Sanger, Joseph W. ; Wang, Jushuo ; Sanger, Jean M.

AbstractThe α‐actin mutation G15R in the nucleotide‐binding pocket of skeletal muscle, causes severe actin myopathy in human skeletal muscles. Expressed in cultured embryonic quail skeletal myotubes, YFP‐G15R‐α‐actin incorporates in sarcomeres in a pattern indistinguishable from wildtype YFP‐α‐actin. However, patches of YFP‐G15R‐α‐actin form, resembling those in patients. Analyses with FRAP of incorporation of YFP‐G15R‐α‐actin showed major differences between fast‐exchanging plus ends of overlapping actin filaments in Z‐bands, versus slow exchanging ends of overlapping thin filaments in the middle of sarcomeres. Wildtype skeletal muscle YFP‐α‐actin shows a faster rate of incorporation at plus ends of F‐actin than at their minus ends. Incorporation of YFP‐G15R‐α‐actin molecules is reduced at plus ends, increased at minus ends. The same relationship of wildtype YFP‐α‐actin incorporation is seen in myofibrils treated with cytochalasin‐D: decreased dynamics at plus ends, increased dynamics at minus ends, and F‐actin aggregates. Speculation: imbalance of normal polarized assembly of F‐actin creates excess monomers that form F‐actin aggregates. Two other severe skeletal muscle YFP‐α‐actin mutations (H40Y and V163L) not in the nucleotide pocket do not affect actin dynamics, and lack F‐actin aggregates. These results indicate that normal α‐actin plus and minus end dynamics are needed to maintain actin filament stability, and avoid F‐actin patches.

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Actin-Accumulation Myopathy

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