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Sarcomeric pattern formation by actin cluster coalescence.

Friedrich BM, Fischer-Friedrich E, Gov NS, Safran SA - PLoS Comput. Biol. (2012)

Bottom Line: Using a one-dimensional computational model of an initially unstriated actin bundle, we show that actin filament treadmilling in the presence of processive plus-end crosslinking provides a simple and robust mechanism for the polarity sorting of actin filaments as well as for the correct localization of myosin filaments.In our simulations, sarcomere spacing is set by filament length prompting tight length control already at early stages of pattern formation.The proposed mechanism could be generic and apply both to premyofibrils and nascent myofibrils in developing muscle cells as well as possibly to striated stress-fibers in non-muscle cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Materials and Interfaces, Weizmann Institute of Science, Rehovot, Israel. ben@pks.mpg.de

ABSTRACT
Contractile function of striated muscle cells depends crucially on the almost crystalline order of actin and myosin filaments in myofibrils, but the physical mechanisms that lead to myofibril assembly remains ill-defined. Passive diffusive sorting of actin filaments into sarcomeric order is kinetically impossible, suggesting a pivotal role of active processes in sarcomeric pattern formation. Using a one-dimensional computational model of an initially unstriated actin bundle, we show that actin filament treadmilling in the presence of processive plus-end crosslinking provides a simple and robust mechanism for the polarity sorting of actin filaments as well as for the correct localization of myosin filaments. We propose that the coalescence of crosslinked actin clusters could be key for sarcomeric pattern formation. In our simulations, sarcomere spacing is set by filament length prompting tight length control already at early stages of pattern formation. The proposed mechanism could be generic and apply both to premyofibrils and nascent myofibrils in developing muscle cells as well as possibly to striated stress-fibers in non-muscle cells.

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Schematic depiction of sarcomeric organization in myofibrils.Actin filaments (blue and red) are grafted at their plus-ends in an -actinin rich crosslinking band, termed the Z-band (green). The repetitive units spanning from one Z-band to the next are referred to as sarcomeres and measure  in length. The myosin band (magenta) is traditionally called A-band, while the myosin-free part of the actin band is called I-band. Numerous auxiliary proteins ensure structural integrity and tune elastic properties.
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pcbi-1002544-g001: Schematic depiction of sarcomeric organization in myofibrils.Actin filaments (blue and red) are grafted at their plus-ends in an -actinin rich crosslinking band, termed the Z-band (green). The repetitive units spanning from one Z-band to the next are referred to as sarcomeres and measure in length. The myosin band (magenta) is traditionally called A-band, while the myosin-free part of the actin band is called I-band. Numerous auxiliary proteins ensure structural integrity and tune elastic properties.

Mentions: The intriguing striations of muscles were first observed more than a century ago [1]. All skeletal and cardiac muscle cells develop striated acto-myosin bundles of striking regularity termed mature myofibrils, which are characterized by a periodic localization of myosin II filaments alternating with crosslinking regions rich in -actinin [2]. An analogous, though less regular, arrangement of actin and myosin filaments can be found in adherent, non-muscle cells that express striated stress fibers [3], [4]. Some developing muscle cells contain similar striated stress-fiber like acto-myosin bundles termed premyofibrils and nascent myofibrils [5]–[7] that have been proposed to represent intermediate structures for the formation of mature myofibrils [8]. Figure 1 depicts the periodic structure of mature myofibrils. Periodically spaced crosslinking regions termed Z-bodies or Z-bands delineate -wide sarcomeric regions that comprise actin filaments of organized polarity and crosslinking myosin filaments in the sarcomere midzone. How are these surprisingly regular structures assembled? Numerous proteins involved in myofibrillogenesis have been identified together with their critical role in several muscle diseases [9]. However, the mechanistic basis for sarcomere self-assembly and the establishment of striated order remains elusive. There is evidence that striated fibers are preceded by unstriated fibers, which lack apparent sarcomeric localization of myosin and crosslinkers. Nascent striations first become visible as agglomerations of the actin crosslinker -actinin, which then grow and change position to establish a regular, periodic spacing [10]. The formation of these early, unstriated bundles requires the parallel alignment of actin filaments, their mutual crosslinking as well as some means to control bundle thickness. Initial bundle formation depends on actin crosslinking, and possibly Onsager nematic alignment and depletion attractions of entropic origin [11], [12], or kinetic effects due to polar actin flow [13]. The thickness of such actin bundles might be kinetically controlled [14]; additionally, geometric frustration effects due to the chirality of actin filaments have been proposed to set bundle thickness [15]–[17]. Here, we focus on the stage of development in which there is already a pre-formed, unstriated bundle of finite thickness and present a mechanism to explain the subsequent emergence of initial sarcomeric order within this unstriated bundle. In muscle cells, subsequent myofibrillar maturation processes, not modeled here, and fine-tuning of actin filament length, e.g. by nebulin [18], [19], drive the transition to final crystalline order.


Sarcomeric pattern formation by actin cluster coalescence.

Friedrich BM, Fischer-Friedrich E, Gov NS, Safran SA - PLoS Comput. Biol. (2012)

Schematic depiction of sarcomeric organization in myofibrils.Actin filaments (blue and red) are grafted at their plus-ends in an -actinin rich crosslinking band, termed the Z-band (green). The repetitive units spanning from one Z-band to the next are referred to as sarcomeres and measure  in length. The myosin band (magenta) is traditionally called A-band, while the myosin-free part of the actin band is called I-band. Numerous auxiliary proteins ensure structural integrity and tune elastic properties.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3369942&req=5

pcbi-1002544-g001: Schematic depiction of sarcomeric organization in myofibrils.Actin filaments (blue and red) are grafted at their plus-ends in an -actinin rich crosslinking band, termed the Z-band (green). The repetitive units spanning from one Z-band to the next are referred to as sarcomeres and measure in length. The myosin band (magenta) is traditionally called A-band, while the myosin-free part of the actin band is called I-band. Numerous auxiliary proteins ensure structural integrity and tune elastic properties.
Mentions: The intriguing striations of muscles were first observed more than a century ago [1]. All skeletal and cardiac muscle cells develop striated acto-myosin bundles of striking regularity termed mature myofibrils, which are characterized by a periodic localization of myosin II filaments alternating with crosslinking regions rich in -actinin [2]. An analogous, though less regular, arrangement of actin and myosin filaments can be found in adherent, non-muscle cells that express striated stress fibers [3], [4]. Some developing muscle cells contain similar striated stress-fiber like acto-myosin bundles termed premyofibrils and nascent myofibrils [5]–[7] that have been proposed to represent intermediate structures for the formation of mature myofibrils [8]. Figure 1 depicts the periodic structure of mature myofibrils. Periodically spaced crosslinking regions termed Z-bodies or Z-bands delineate -wide sarcomeric regions that comprise actin filaments of organized polarity and crosslinking myosin filaments in the sarcomere midzone. How are these surprisingly regular structures assembled? Numerous proteins involved in myofibrillogenesis have been identified together with their critical role in several muscle diseases [9]. However, the mechanistic basis for sarcomere self-assembly and the establishment of striated order remains elusive. There is evidence that striated fibers are preceded by unstriated fibers, which lack apparent sarcomeric localization of myosin and crosslinkers. Nascent striations first become visible as agglomerations of the actin crosslinker -actinin, which then grow and change position to establish a regular, periodic spacing [10]. The formation of these early, unstriated bundles requires the parallel alignment of actin filaments, their mutual crosslinking as well as some means to control bundle thickness. Initial bundle formation depends on actin crosslinking, and possibly Onsager nematic alignment and depletion attractions of entropic origin [11], [12], or kinetic effects due to polar actin flow [13]. The thickness of such actin bundles might be kinetically controlled [14]; additionally, geometric frustration effects due to the chirality of actin filaments have been proposed to set bundle thickness [15]–[17]. Here, we focus on the stage of development in which there is already a pre-formed, unstriated bundle of finite thickness and present a mechanism to explain the subsequent emergence of initial sarcomeric order within this unstriated bundle. In muscle cells, subsequent myofibrillar maturation processes, not modeled here, and fine-tuning of actin filament length, e.g. by nebulin [18], [19], drive the transition to final crystalline order.

Bottom Line: Using a one-dimensional computational model of an initially unstriated actin bundle, we show that actin filament treadmilling in the presence of processive plus-end crosslinking provides a simple and robust mechanism for the polarity sorting of actin filaments as well as for the correct localization of myosin filaments.In our simulations, sarcomere spacing is set by filament length prompting tight length control already at early stages of pattern formation.The proposed mechanism could be generic and apply both to premyofibrils and nascent myofibrils in developing muscle cells as well as possibly to striated stress-fibers in non-muscle cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Materials and Interfaces, Weizmann Institute of Science, Rehovot, Israel. ben@pks.mpg.de

ABSTRACT
Contractile function of striated muscle cells depends crucially on the almost crystalline order of actin and myosin filaments in myofibrils, but the physical mechanisms that lead to myofibril assembly remains ill-defined. Passive diffusive sorting of actin filaments into sarcomeric order is kinetically impossible, suggesting a pivotal role of active processes in sarcomeric pattern formation. Using a one-dimensional computational model of an initially unstriated actin bundle, we show that actin filament treadmilling in the presence of processive plus-end crosslinking provides a simple and robust mechanism for the polarity sorting of actin filaments as well as for the correct localization of myosin filaments. We propose that the coalescence of crosslinked actin clusters could be key for sarcomeric pattern formation. In our simulations, sarcomere spacing is set by filament length prompting tight length control already at early stages of pattern formation. The proposed mechanism could be generic and apply both to premyofibrils and nascent myofibrils in developing muscle cells as well as possibly to striated stress-fibers in non-muscle cells.

Show MeSH