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Talin Is Required Continuously for Cardiomyocyte Remodeling during Heart Growth in Drosophila.

Bogatan S, Cevik D, Demidov V, Vanderploeg J, Panchbhaya A, Vitkin A, Jacobs JR - PLoS ONE (2015)

Bottom Line: Retracted myofibrils cannot regenerate appositions to adjacent cells after restoration of normal Talin expression, and the resulting deficit reduces heart contraction and lifespan.Reduction of Talin during heart remodeling after hatching or during metamorphosis results in pervasive degeneration of cell contacts, myofibril length and number, for which restored Talin expression is insufficient for regeneration.Resultant dilated cardiomyopathy results in a fibrillating heart with poor rhythmicity.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, McMaster University, Hamilton, ON, Canada.

ABSTRACT
Mechanotransduction of tension can govern the remodeling of cardiomyocytes during growth or cardiomyopathy. Tension is signaled through the integrin adhesion complexes found at muscle insertions and costameres but the relative importance of signalling during cardiomyocyte growth versus remodelling has not been assessed. Employing the Drosophila cardiomyocyte as a genetically amenable model, we depleted the levels of Talin, a central component of the integrin adhesion complex, at different stages of heart growth and remodeling. We demonstrate a continuous requirement for Talin during heart growth to maintain the one-to-one apposition of myofibril ends between cardiomyocytes. Retracted myofibrils cannot regenerate appositions to adjacent cells after restoration of normal Talin expression, and the resulting deficit reduces heart contraction and lifespan. Reduction of Talin during heart remodeling after hatching or during metamorphosis results in pervasive degeneration of cell contacts, myofibril length and number, for which restored Talin expression is insufficient for regeneration. Resultant dilated cardiomyopathy results in a fibrillating heart with poor rhythmicity. Cardiomyocytes have poor capacity to regenerate deficits in myofibril orientation and insertion, despite an ongoing capacity to remodel integrin based adhesions.

No MeSH data available.


Related in: MedlinePlus

Cardiomyocytes do not re-connect after transient reduction of Talin function.In a wildtype adult, 6 days after eclosion, phalloidin labeled contractile fibres encompassed the entire heart, and integrin concentrated at cell insertions and the midline (arrowhead, A). This morphology was not altered after a further 6 weeks of aging (arrowhead, F). Talin was transiently depleted during larval, pupal or adult stages as shown by the coloured schema at the bottom of each panel, and stages labeled in (A). UAS-talin RNAi; Hand-Gal4, tub- Gal80ts flies were at 18°C during grey timeline, and Talin levels were normal., Hearts express the RNAi transgene, and deplete Talin levels at 29°C during the green timeline. Depletion during L1 created large gaps in myofibril coverage seen in the adult (B). Depletion during L2 created small gaps, filled with a broadened zone of integrin adhesion to the heart ECM (C). Depletion during pupal stages only generated an intermediate phenotype (D), comparable to depletion during L2, L3 and pupal stages combined (E). Depletion of Talin for 6 weeks of adulthood triggered small changes in the width of integrin labeled insertions (G). In contrast, gaps triggered in L2 persisted in 6 week old adults (H). Confocal projections of immunolabled adult heart dissections.
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pone.0131238.g004: Cardiomyocytes do not re-connect after transient reduction of Talin function.In a wildtype adult, 6 days after eclosion, phalloidin labeled contractile fibres encompassed the entire heart, and integrin concentrated at cell insertions and the midline (arrowhead, A). This morphology was not altered after a further 6 weeks of aging (arrowhead, F). Talin was transiently depleted during larval, pupal or adult stages as shown by the coloured schema at the bottom of each panel, and stages labeled in (A). UAS-talin RNAi; Hand-Gal4, tub- Gal80ts flies were at 18°C during grey timeline, and Talin levels were normal., Hearts express the RNAi transgene, and deplete Talin levels at 29°C during the green timeline. Depletion during L1 created large gaps in myofibril coverage seen in the adult (B). Depletion during L2 created small gaps, filled with a broadened zone of integrin adhesion to the heart ECM (C). Depletion during pupal stages only generated an intermediate phenotype (D), comparable to depletion during L2, L3 and pupal stages combined (E). Depletion of Talin for 6 weeks of adulthood triggered small changes in the width of integrin labeled insertions (G). In contrast, gaps triggered in L2 persisted in 6 week old adults (H). Confocal projections of immunolabled adult heart dissections.

Mentions: Unexpectedly, the period of greatest vulnerability to reduced Talin function was the first larval instar. In contrast to larvae raised entirely at 18°C (Fig 4A), larvae shifted to 29°C during the first instar had cardiomyocytes that were largely detached from one another, and not regularly placed along the length of the heart (Fig 4B). Similarly, these hearts were the most dilated, to more than twice the control cross-sectional area at diastole (Fig 5A). Resumption of Talin expression following first instar heat treatment could be delayed by the perdurance of Talin dsRNA, and the rate of Talin synthesis. Therefore we also looked at Talin depletion during the second and third instar, a period of tremendous growth in the heart. Depletion of Talin during second instar resulted in minor cardiomyocyte defects. Although the myocytes have enlarged during the larval growth, the myofibrils of adjacent myocytes no longer connect or align at narrow myocyte junctions, analogous to the intercalated disc of vertebrates (Fig 4C). This deficit shows no recovery subsequent to metamorphosis. Cardiomyocytes have tight apposition at the midline of controls raised at 18°C for 6 weeks (Fig 4F). Drosophila cardiomyocytes lack the uniform midline apposition if depleted in Talin only during second instar (Fig 4H). The gaps between myocytes are filled with expanded integrin adhesions, also producing an irregular alignment of cell appositions at the midline and a loss of myofibril alignment. Depletion of Talin during metamorphosis resulted in greater myofibril retraction, comparable to that seen with first instar depletion, but without the accompanying dilation of the vessel (Fig 4D and 4E). The midline apposition of cardiomyocytes was slightly widened by Talin depletion only during adulthood (Fig 4G), suggesting that turnover of Talin was reduced in post—growth myocytes. These data suggest that Talin is required at all pre-adult stages, but that the morphological consequences are more severe during remodelling rather than growth phases of development (summarised in S3 File). More significantly, early developmental defects in myocyte contacts and myofibril architecture are not repaired as the cardiomyocytes grow or remodel during metamorphosis.


Talin Is Required Continuously for Cardiomyocyte Remodeling during Heart Growth in Drosophila.

Bogatan S, Cevik D, Demidov V, Vanderploeg J, Panchbhaya A, Vitkin A, Jacobs JR - PLoS ONE (2015)

Cardiomyocytes do not re-connect after transient reduction of Talin function.In a wildtype adult, 6 days after eclosion, phalloidin labeled contractile fibres encompassed the entire heart, and integrin concentrated at cell insertions and the midline (arrowhead, A). This morphology was not altered after a further 6 weeks of aging (arrowhead, F). Talin was transiently depleted during larval, pupal or adult stages as shown by the coloured schema at the bottom of each panel, and stages labeled in (A). UAS-talin RNAi; Hand-Gal4, tub- Gal80ts flies were at 18°C during grey timeline, and Talin levels were normal., Hearts express the RNAi transgene, and deplete Talin levels at 29°C during the green timeline. Depletion during L1 created large gaps in myofibril coverage seen in the adult (B). Depletion during L2 created small gaps, filled with a broadened zone of integrin adhesion to the heart ECM (C). Depletion during pupal stages only generated an intermediate phenotype (D), comparable to depletion during L2, L3 and pupal stages combined (E). Depletion of Talin for 6 weeks of adulthood triggered small changes in the width of integrin labeled insertions (G). In contrast, gaps triggered in L2 persisted in 6 week old adults (H). Confocal projections of immunolabled adult heart dissections.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482443&req=5

pone.0131238.g004: Cardiomyocytes do not re-connect after transient reduction of Talin function.In a wildtype adult, 6 days after eclosion, phalloidin labeled contractile fibres encompassed the entire heart, and integrin concentrated at cell insertions and the midline (arrowhead, A). This morphology was not altered after a further 6 weeks of aging (arrowhead, F). Talin was transiently depleted during larval, pupal or adult stages as shown by the coloured schema at the bottom of each panel, and stages labeled in (A). UAS-talin RNAi; Hand-Gal4, tub- Gal80ts flies were at 18°C during grey timeline, and Talin levels were normal., Hearts express the RNAi transgene, and deplete Talin levels at 29°C during the green timeline. Depletion during L1 created large gaps in myofibril coverage seen in the adult (B). Depletion during L2 created small gaps, filled with a broadened zone of integrin adhesion to the heart ECM (C). Depletion during pupal stages only generated an intermediate phenotype (D), comparable to depletion during L2, L3 and pupal stages combined (E). Depletion of Talin for 6 weeks of adulthood triggered small changes in the width of integrin labeled insertions (G). In contrast, gaps triggered in L2 persisted in 6 week old adults (H). Confocal projections of immunolabled adult heart dissections.
Mentions: Unexpectedly, the period of greatest vulnerability to reduced Talin function was the first larval instar. In contrast to larvae raised entirely at 18°C (Fig 4A), larvae shifted to 29°C during the first instar had cardiomyocytes that were largely detached from one another, and not regularly placed along the length of the heart (Fig 4B). Similarly, these hearts were the most dilated, to more than twice the control cross-sectional area at diastole (Fig 5A). Resumption of Talin expression following first instar heat treatment could be delayed by the perdurance of Talin dsRNA, and the rate of Talin synthesis. Therefore we also looked at Talin depletion during the second and third instar, a period of tremendous growth in the heart. Depletion of Talin during second instar resulted in minor cardiomyocyte defects. Although the myocytes have enlarged during the larval growth, the myofibrils of adjacent myocytes no longer connect or align at narrow myocyte junctions, analogous to the intercalated disc of vertebrates (Fig 4C). This deficit shows no recovery subsequent to metamorphosis. Cardiomyocytes have tight apposition at the midline of controls raised at 18°C for 6 weeks (Fig 4F). Drosophila cardiomyocytes lack the uniform midline apposition if depleted in Talin only during second instar (Fig 4H). The gaps between myocytes are filled with expanded integrin adhesions, also producing an irregular alignment of cell appositions at the midline and a loss of myofibril alignment. Depletion of Talin during metamorphosis resulted in greater myofibril retraction, comparable to that seen with first instar depletion, but without the accompanying dilation of the vessel (Fig 4D and 4E). The midline apposition of cardiomyocytes was slightly widened by Talin depletion only during adulthood (Fig 4G), suggesting that turnover of Talin was reduced in post—growth myocytes. These data suggest that Talin is required at all pre-adult stages, but that the morphological consequences are more severe during remodelling rather than growth phases of development (summarised in S3 File). More significantly, early developmental defects in myocyte contacts and myofibril architecture are not repaired as the cardiomyocytes grow or remodel during metamorphosis.

Bottom Line: Retracted myofibrils cannot regenerate appositions to adjacent cells after restoration of normal Talin expression, and the resulting deficit reduces heart contraction and lifespan.Reduction of Talin during heart remodeling after hatching or during metamorphosis results in pervasive degeneration of cell contacts, myofibril length and number, for which restored Talin expression is insufficient for regeneration.Resultant dilated cardiomyopathy results in a fibrillating heart with poor rhythmicity.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, McMaster University, Hamilton, ON, Canada.

ABSTRACT
Mechanotransduction of tension can govern the remodeling of cardiomyocytes during growth or cardiomyopathy. Tension is signaled through the integrin adhesion complexes found at muscle insertions and costameres but the relative importance of signalling during cardiomyocyte growth versus remodelling has not been assessed. Employing the Drosophila cardiomyocyte as a genetically amenable model, we depleted the levels of Talin, a central component of the integrin adhesion complex, at different stages of heart growth and remodeling. We demonstrate a continuous requirement for Talin during heart growth to maintain the one-to-one apposition of myofibril ends between cardiomyocytes. Retracted myofibrils cannot regenerate appositions to adjacent cells after restoration of normal Talin expression, and the resulting deficit reduces heart contraction and lifespan. Reduction of Talin during heart remodeling after hatching or during metamorphosis results in pervasive degeneration of cell contacts, myofibril length and number, for which restored Talin expression is insufficient for regeneration. Resultant dilated cardiomyopathy results in a fibrillating heart with poor rhythmicity. Cardiomyocytes have poor capacity to regenerate deficits in myofibril orientation and insertion, despite an ongoing capacity to remodel integrin based adhesions.

No MeSH data available.


Related in: MedlinePlus