The vertebrate muscle Z-disc: sarcomere anchor for structure and signalling

Luther, Pradeep K.

doi:10.1007/s10974-009-9189-6

Cited by 202 publications

(196 citation statements)

References 87 publications

(161 reference statements)

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“…In our contractions, forces exceeded the maximal isometric forces by up to 150% ( figure 3, black solid lines). Vertebrate muscle Z-discs transmit the forces between sarcomeres via a varying number of a-actinin-layers [59]. Z-discs in fast-twitch fibred muscles transmit these forces via a lower number of a-actinins.…”

Section: Discussionmentioning

confidence: 99%

The active force–length relationship is invisible during extensive eccentric contractions in skinned skeletal muscle fibres

et al. 2017

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In contrast to experimentally observed progressive forces in eccentric contractions, cross-bridge and sliding-filament theories of muscle contraction predict that varying myofilament overlap will lead to increases and decreases in active force during eccentric contractions. Non-cross-bridge contributions potentially explain the progressive total forces. However, it is not clear whether underlying abrupt changes in the slope of the nonlinear forcelength relationship are visible in long isokinetic stretches, and in which proportion cross-bridges and non-cross-bridges contribute to muscle force. Here, we show that maximally activated single skinned rat muscle fibres behave (almost across the entire working range) like linear springs. The force slope is about three times the maximum isometric force per optimal length. Cross-bridge and non-cross-bridge contributions to the muscle force were investigated using an actomyosin inhibitor. The experiments revealed a nonlinear progressive contribution of non-cross-bridge forces and suggest a nonlinear cross-bridge contribution similar to the active force-length relationship (though with increased optimal length and maximum isometric force). The linear muscle behaviour might significantly reduce the control effort. Moreover, the observed slight increase in slope with initial length is in accordance with current models attributing the non-cross-bridge force to titin.

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Section: Discussionmentioning

confidence: 99%

The active force–length relationship is invisible during extensive eccentric contractions in skinned skeletal muscle fibres

et al. 2017

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“…The number of Z-repeats found in titin depends on the isoform and ranges between two and seven across all species (20), with repeats T1 and T7 being always present. Joseph et al (22) assessed affinities of all repeats to α-actinin and found measurable affinities to α-actinin 2 for T1, T3, and T7.…”

Section: Discussionmentioning

confidence: 99%

“…S1) (18, 19). Upon activation of α-actinin in the Z-disk by phosphatidylinositol 4,5-biphosphate (PIP 2 ), EF3-4 is released from the neck and binding of titin can be achieved in this open conformation of α-actinin.In humans, the isoforms of titin exhibit four to seven Z-repeats (15,16,20). The structure of the EF3-4 hands complex with titin Z-repeat 7 shows the bound Z-repeat in an α-helical conformation (21).…”

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confidence: 99%

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α-Actinin/titin interaction: A dynamic and mechanically stable cluster of bonds in the muscle Z-disk

Grison

Merkel

Košťan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Stable anchoring of titin within the muscle Z-disk is essential for preserving muscle integrity during passive stretching. One of the main candidates for anchoring titin in the Z-disk is the actin crosslinker α-actinin. The calmodulin-like domain of α-actinin binds to the Z-repeats of titin. However, the mechanical and kinetic properties of this important interaction are still unknown. Here, we use a dual-beam optical tweezers assay to study the mechanics of this interaction at the single-molecule level. A single interaction of α-actinin and titin turns out to be surprisingly weak if force is applied. Depending on the direction of force application, the unbinding forces can more than triple. Our results suggest a model where multiple α-actinin/Z-repeat interactions cooperate to ensure long-term stable titin anchoring while allowing the individual components to exchange dynamically.M uscle is the tissue that is constantly subjected to high mechanical loads. Whereas thick and thin filaments are responsible for active force production, the passive elasticity of muscle is dominated by titin/connectin filaments (1). Hence, under passive stretching conditions the integrity of muscle relies on titin's being firmly anchored within the sarcomere, preventing the interdigitated muscle filaments from falling apart (Fig. 1A). Whereas titin is firmly attached to thick filaments in the A-band and the M-line (2-6), it is much less clear how stable anchoring is achieved in the Z-disk, where adjacent sarcomeres overlap. The superstable titin/telethonin interaction within the Z-disk was considered important for titin anchoring (7-9), but knockout mutants later showed that it is not essential for muscle integrity (10-12). Apart from a direct interaction between actin filaments and titin at the Z-disk edge (13), the most prominent candidate for the anchoring of titin within the Z-disk is its interaction with α-actinin (Fig. 1B) (6,12,14).Four isoforms of human α-actinin have been identified: the calcium-insensitive muscle isoforms 2 and 3, which cross-link actin filaments in sarcomere-delimiting Z-disk complexes, and calcium-sensitive nonmuscle isoforms 1 and 4. α-Actinin is an antiparallel homodimer whose most prominent task is crosslinking actin filaments of neighboring sarcomeres in the Z-disk ( Fig. 1B; reviewed in ref. 14). In each subunit, a flexible region called the neck separates the actin binding domain (ABD) from four spectrin-like repeats (SR) forming the rod region (Fig. 1B and Fig. S1). The rod regions of the two subunits interact and provide a rigid spacer between the actin filaments. At the other end of each subunit a calmodulin-like domain (CaMD) formed by two pairs of EF-hands (EF1-2 and EF3-4) is able to bind a Z-disk region of titin formed by the so-called Z-repeats (15-17). The current model for α-actinin 2 dynamic regulation suggests that EF3-4 hands of one subunit bind to the neck region of the juxtaposed subunit, thus not being available for the interaction with titin Z-repeats (Fig. S1) (18, 19). Upon activ...

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“…Thin filaments from neighbouring sarcomeres are anchored in the Z-disc by α-actinin and other cross-linking proteins, and thick filaments are held in position by cross-links at the M-line in the middle of the sarcomere (Agarkova and Perriard, 2005;Luther, 2009). The register of thick filaments is also maintained by elastic links between the ends of the filaments and the Z-disc (Horowits and Podolsky, 1987;Tskhovrebova and Trinick, 2003).…”

Section: Introductionmentioning

confidence: 99%

Binding partners of the kinase domains inDrosophilaobscurin and their effect on the structure of the flight muscle

Katzemich

West

Fukuzawa

et al. 2015

Journal of Cell Science

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Drosophila obscurin (Unc-89) is a titin-like protein in the M-line of the muscle sarcomere. Obscurin has two kinase domains near the C-terminus, both of which are predicted to be inactive. We have identified proteins binding to the kinase domains. Kinase domain 1 bound Bällchen (Ball, an active kinase), and both kinase domains 1 and 2 bound MASK (a 400-kDa protein with ankyrin repeats). Ball was present in the Z-disc and M-line of the indirect flight muscle (IFM) and was diffusely distributed in the sarcomere. MASK was present in both the M-line and the Z-disc. Reducing expression of Ball or MASK by siRNA resulted in abnormalities in the IFM, including missing M-lines and multiple Z-discs. Obscurin was still present, suggesting that the kinase domains act as a scaffold binding Ball and MASK. Unlike obscurin in vertebrate skeletal muscle, Drosophila obscurin is necessary for the correct assembly of the IFM sarcomere. We show that Ball and MASK act downstream of obscurin, and both are needed for development of a well defined M-line and Z-disc. The proteins have not previously been identified in Drosophila muscle.

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The vertebrate muscle Z-disc: sarcomere anchor for structure and signalling

Cited by 202 publications

References 87 publications

The active force–length relationship is invisible during extensive eccentric contractions in skinned skeletal muscle fibres

The active force–length relationship is invisible during extensive eccentric contractions in skinned skeletal muscle fibres

α-Actinin/titin interaction: A dynamic and mechanically stable cluster of bonds in the muscle Z-disk

Binding partners of the kinase domains inDrosophilaobscurin and their effect on the structure of the flight muscle

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