Muscle Contraction: Too much of a good thing
Our muscles help us to move, eat, breathe and pump blood through our body. The skeletal and heart muscles of vertebrates consist of bundles of muscle fibers, with each fiber containing thousands of smaller structures called myofibrils. Within these myofibrils, thick myosin filaments and thin actin filaments can slide past each other to change the length of the muscle. This involves a part of a myosin filament, called the myosin head, 'grabbing hold' of an actin filament.
Controlling the interactions between the myosin heads and actin is a finely tuned and highly regulated process, and even small changes to it can lead to dysfunction and disease. For example, in a condition called hypertrophic cardiomyopathy, mutations in the myosin head can cause the walls of the heart to thicken, ultimately restricting the outflow of blood (Garfinkel et al., 2018). So far, it has been unclear how the mutations can cause these problems. Now, in eLife, Sanford Bernstein, Douglas Swank and colleagues at San Diego State University, Rensselaer Polytechnic Institute and Johns Hopkins University – including William Kronert as first author – report the surprising finding that a mutation in the motor portion of the myosin head that causes human hypertrophic cardiomyopathy can lead to degeneration of the flight muscles as well as the dysfunction of the heart tube in fruit flies (Kronert et al., 2018).
What appears to underlie this seemingly perplexing result is a loss of proper interactions either within myosin heads or, possibly, between the myosin heads and other components of the myosin filament. These interactions normally lead to the myosin heads being packed onto the ‘backbone’ of the myosin filament in a way that restricts their interactions with the actin filaments.
The myosin head contains a motor domain, a regulatory light chain and an essential light chain. The key structural insights into the packing of the myosin heads came from studying the regulation of smooth muscle myosin in vertebrates, which is inactive unless the regulatory light chain is phosphorylated (Wendt et al., 2001). This work revealed asymmetric interactions (known as the 'interacting head motif’) between neighboring myosin heads, which trapped both heads in inactive conformations: the actin binding site of one head was blocked by binding to the other in a way that prevented the latter from releasing the products of ATP hydrolysis when it interacted with actin (Figure 1). Interacting head motifs have also been found in the skeletal muscle of tarantulas, the heart muscles of vertebrates, and even in primitive animals that do not form muscles (Alamo et al., 2016; Woodhead et al., 2005; Lee et al., 2018; Zoghbi et al., 2008).
In an energy conserving ‘super-relaxed state’, myosin is trapped in a state with very low basal ATPase activity (Stewart et al., 2010). This appears to be a mechanism to stabilize myosin in its ‘pre-powerstroke’ state, in which inorganic phosphate and ADP are confined within the myosin head. Kronert et al. suggest that this pre-powerstroke state is destabilized by the mutation they were studying.
The researchers used fruit flies with a specific mutation on the side of the myosin head, called K146N, which causes thickening of the heart wall in humans. In the flies, the mutation leads to a degenerated heart tube and flight muscles. For both humans and flies, the problem appears to be the same: too many myosin heads interact during contraction and attach to actin for longer than usual, leading to hyperactivation, damage and disorder in the muscle. Myosin was able to create more force, while the movement of actin slowed down. Over time, the increased cost of performing work caused the muscles to degenerate. Although this does not lead to hypertrophy of the flight muscles – as it does in the human heart – there is decreased relaxation and restriction of the heart tube in the flies, paralleling human hypertrophic cardiomyopathy.
The ‘myosin mesa’ theory hypothesizes that many of the mutations causing hypertrophic cardiomyopathy are surface mutations that interfere with the formation and/or stabilization of the interacting head motif (Trivedi et al., 2018). It also proposes that a subset of these mutations might lead to interactions with another protein of the thick filament of the heart muscle, the myosin-binding protein C, which could help stabilize the interactions between the two myosin heads in the interacting head motif. This in turn could explain why mutations in myosin-binding protein C can also cause hypertrophic cardiomyopathy. Based on these concepts, a drug that stabilizes the super-relaxed state and the interacting head motif is being developed for the treatment of human hypertrophic cardiomyopathy (Anderson et al., 2018).
All in all, fruit flies may be a surprisingly good model to test the effects of mutations associated with human hypertrophic cardiomyopathy, apart from those that may interact directly with myosin-binding protein C, which is not present in fruit flies. However, the major significance of the work is that it underscores that since the super-relaxed state and the packing of interacting head motifs onto thick filaments is conserved throughout the evolution of muscle, it is likely that their functions – which would be to control the number of myosin heads available to interact with actin when the muscle is activated, and to lower the energetic cost when the muscle is relaxed – are also conserved.
References
-
Genetic pathogenesis of hypertrophic and dilated cardiomyopathyHeart Failure Clinics 14:139–146.https://doi.org/10.1016/j.hfc.2017.12.004
Article and author information
Author details
Publication history
Copyright
© 2018, Sweeney
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 3,639
- views
-
- 135
- downloads
-
- 3
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Cell Biology
Aggregation of mutant forms of Huntingtin is the underlying feature of neurodegeneration observed in Huntington’s disorder. In addition to neurons, cellular processes in non-neuronal cell types are also shown to be affected. Cells expressing neurodegeneration–associated mutant proteins show altered uptake of ligands, suggestive of impaired endocytosis, in a manner as yet unknown. Using live cell imaging, we show that clathrin-mediated endocytosis (CME) is affected in Drosophila hemocytes and mammalian cells containing Huntingtin aggregates. This is also accompanied by alterations in the organization of the actin cytoskeleton resulting in increased cellular stiffness. Further, we find that Huntingtin aggregates sequester actin and actin-modifying proteins. Overexpression of Hip1 or Arp3 (actin-interacting proteins) could restore CME and cellular stiffness in cells containing Huntingtin aggregates. Neurodegeneration driven by pathogenic Huntingtin was also rescued upon overexpression of either Hip1 or Arp3 in Drosophila. Examination of other pathogenic aggregates revealed that TDP-43 also displayed defective CME, altered actin organization and increased stiffness, similar to pathogenic Huntingtin. Together, our results point to an intimate connection between dysfunctional CME, actin misorganization and increased cellular stiffness caused by alteration in the local intracellular environment by pathogenic aggregates.
-
- Cell Biology
- Developmental Biology
How cells regulate the size of their organelles remains a fundamental question in cell biology. Cilia, with their simple structure and surface localization, provide an ideal model for investigating organelle size control. However, most studies on cilia length regulation are primarily performed on several single-celled organisms. In contrast, the mechanism of length regulation in cilia across diverse cell types within multicellular organisms remains a mystery. Similar to humans, zebrafish contain diverse types of cilia with variable lengths. Taking advantage of the transparency of zebrafish embryos, we conducted a comprehensive investigation into intraflagellar transport (IFT), an essential process for ciliogenesis. By generating a transgenic line carrying Ift88-GFP transgene, we observed IFT in multiple types of cilia with varying lengths. Remarkably, cilia exhibited variable IFT speeds in different cell types, with longer cilia exhibiting faster IFT speeds. This increased IFT speed in longer cilia is likely not due to changes in common factors that regulate IFT, such as motor selection, BBSome proteins, or tubulin modification. Interestingly, longer cilia in the ear cristae tend to form larger IFT compared to shorter spinal cord cilia. Reducing the size of IFT particles by knocking down Ift88 slowed IFT speed and resulted in the formation of shorter cilia. Our study proposes an intriguing model of cilia length regulation via controlling IFT speed through the modulation of the size of the IFT complex. This discovery may provide further insights into our understanding of how organelle size is regulated in higher vertebrates.