Drosophila model of myosin myopathy rescued by overexpression of a TRIM-protein family member

Abstract

Myosin is a molecular motor indispensable for body movement and heart contractility. Apart from pure cardiomyopathy, mutations in encoding slow/β-cardiac myosin heavy chain also cause skeletal muscle disease with or without cardiac involvement. Mutations within the α-helical rod domain of are mainly associated with Laing distal myopathy. To investigate the mechanisms underlying the pathology of the recurrent causative mutation (K1729del), we have developed a model of Laing distal myopathy by genomic engineering of the locus. Homozygous animals die during larval/pupal stages, and both homozygous and heterozygous larvae display reduced muscle function. Flies expressing only in indirect flight and jump muscles, and heterozygous animals, were flightless, with reduced movement and decreased lifespan. Sarcomeres of mutant indirect flight muscles and larval body wall muscles were disrupted with clearly disorganized muscle filaments. Homozygous larvae also demonstrated structural and functional impairments in heart muscle, which were not observed in heterozygous animals, indicating a dose-dependent effect of the mutated allele. The impaired jump and flight ability and the myopathy of indirect flight and leg muscles associated with were fully suppressed by expression of Abba/Thin, an E3-ligase that is essential for maintaining sarcomere integrity. This model of Laing distal myopathy in recapitulates certain morphological phenotypic features seen in Laing distal myopathy patients with the recurrent K1729del mutation. Our observations that Abba/Thin modulates these phenotypes suggest that manipulation of Abba/Thin activity levels may be beneficial in Laing distal myopathy.

Come Together: Protein Assemblies, Aggregates and the Sarcostat at the Heart of Cardiac Myocyte Homeostasis

“…In addition to the stoichiometric argument, the energetic argument to be able to draw on a local pool of protein, rather than solely relying on newly synthesized protein adds tremendous flexibility during states of metabolic stress when transcription and translation may be affected. Furthermore, augmentation of the protein quality control machinery (both proteasomal as well as the autophagylysosomal pathway) is associated with benefits and sarcomere recovery in a variety of heart failure models associated with sarcomere dysfunction even in the absence of correction of the primary genetic abnormality (such as mutations in MYH7, desmin, and CryAB) (Li et al, 2011;Pattison et al, 2011;Ranek et al, 2013;Gupta et al, 2014;McLendon et al, 2014;Cabet et al, 2015;Su et al, 2015;Dahl-Halvarsson et al, 2018;. Thus, various elements of the "sarcostat" are in dynamic equilibrium, whereby perturbations in one element (either genetic or environmental) induce structural and functional abnormalities, and therapeutic targeting of this inciting stimulus or another balancing node can restore homeostasis.…”

Genetic Control of Muscle Diversification and Homeostasis: Insights from Drosophila

“…A study has shown that the formation of large aggregates in muscles similar to those seen in human patients with ZASP mutations is caused by an imbalance in the levels of Zasp isoforms [ 246 ]. Dahl-Halvarsson et al showed that the overexpression of the Thin protein, a homolog of the human TRIM family of proteins that is implicated in maintaining sarcomeric integrity, could alleviate LDM-like phenotypes [ 305 ].…”

Cored in the act: the use of models to understand core myopathies

“…Finally, there are currently no models for MYH7, TTN or ACTA1 mutations, which cause a subset of MmD with cardiac involvement (Chauveau et al, 2014;Cullup et al, 2012;Kaindl, 2004). However, Drosophila with Laing-distal-myopathy-associated L1729del myh7 mutations develop myofibril disruption, cores and mitochondrial abnormalities, further blurring the genotypephenotype boundaries (Dahl-Halvarsson et al, 2018).…”