Microtubule dynamics control the direction of cardiomyocyte growth.
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| Title: | Microtubule dynamics control the direction of cardiomyocyte growth. |
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| Authors: | Scarborough, Emily A. (AUTHOR), Randell, Rani M. (AUTHOR), Uchida, Keita (AUTHOR), Stone, Kathlyene R. (AUTHOR), Margulies, Kenneth B. (AUTHOR), Prosser, Benjamin L. (AUTHOR) |
| Source: | Science. 5/14/2026, Vol. 392 Issue 6799, p1-16. 16p. |
| Subjects: | Microtubules, Cardiac hypertrophy, Ventricular remodeling, Heart dilatation, Heart development, Nucleocytoplasmic interactions, Cell junctions, Protein synthesis |
| Abstract: | The adult heart grows by the addition of sarcomeres along the length or width of individual cardiomyocytes, yet how directional growth is spatially coordinated remains unclear. We found that microtubule dynamics could act as a toggle to direct cardiomyocyte growth. Increasing microtubule stability drove cellular widening, concomitant with redirecting messenger RNA (mRNA) export and translation along the width of the cell and reinforcement of the intercalated disc. Conversely, decreasing microtubule stability promoted cellular lengthening, disrupting the intercalated disc and biasing translation and incorporation of new sarcomeric protein toward this structure. Notably, disrupting intercalated disc adhesion was sufficient for cardiomyocyte elongation yet dispensable for cardiomyocyte widening. Thus, the heart coordinates local translation and structural remodeling to orchestrate bidirectional growth. Editor's summary: To adapt to stress, heart walls can thicken or thin, a process driven by the thickening or lengthening of heart muscle cells. However, how muscle cells choose a direction of growth has remained unclear. Scarborough et al. identified microtubule dynamics as a molecular toggle that directs cardiac growth. Stabilizing microtubules redirected RNA export and protein synthesis toward augmenting the cells' width, whereas reinforcing cell-cell junctions promoted cellular thickening. Destabilizing microtubules had the opposite effect, weakening these junctions and permitting cellular elongation. Thus, microtubules direct cardiac geometry by coupling the location of protein synthesis with the remodeling of cell-cell contacts. —Stella M. Hurtley INTRODUCTION: The heart adapts to stress by altering the thickness and geometry of the myocardial walls. This organ-level remodeling is driven primarily by the growth of individual heart muscle cells, or cardiomyocytes. Cardiomyocytes can add contractile units along their width or length to promote wall thickening or thinning—known as concentric and eccentric remodeling, respectively. Growth along these different axes produces fundamentally distinct functional adaptations and pathological consequences, yet the molecular mechanisms that spatially coordinate cardiac growth have remained unclear. RATIONALE: Microtubules are dynamic cytoskeletal filaments that organize intracellular transport, RNA localization, and protein synthesis and are required for generalized cardiac growth. Bidirectional alterations in microtubule stability have been linked to distinct patterns of cardiac remodeling, but whether microtubules actively direct growth, and through which mechanisms, remains unknown. Disparate findings have implicated restructuring of cell-cell contacts at the intercalated disc to eccentric remodeling in mouse and patient tissues. We thus hypothesized that microtubule dynamics may act as a molecular toggle to direct cardiomyocyte thickening or elongation, perhaps in part through structural remodeling of the intercalated disc. RESULTS: Using primary cardiomyocytes and animal models with pharmacologic and genetic manipulation of microtubule dynamics, we found that microtubule stability controlled the direction of cardiac growth through at least two primary mechanisms. In vitro, we found that stabilizing microtubules increased cardiomyocyte width, whereas microtubule destabilization caused cellular lengthening. Mechanistically, microtubule stabilization shifted mRNA export to the nuclear short axis to redirect mRNA and protein synthesis along the width of the cell—a process dependent on the interaction between microtubules and nuclear envelope proteins. Furthermore, microtubule stabilization rapidly reinforced the intercalated disc, whereas microtubule destabilization led to a loss of intercalated disc structure. Disrupting intercalated disc adhesion was sufficient to cause cardiomyocyte elongation and biased the incorporation of newly synthesized contractile proteins toward the cell ends. In vivo, mouse models of cardiac remodeling with increased microtubule stability exhibited relocalized translation and compact intercalated discs with heart wall thickening, whereas microtubule destabilization led to weakening of the intercalated disc and heart wall thinning. Human heart samples mirrored these patterns, where intercalated disc compaction correlated with cardiomyocyte elongation, heart chamber dilation, and worsening cardiac function. CONCLUSION: We propose a model of bidirectional cardiac hypertrophy mediated by the microtubule cytoskeleton. Altered microtubule dynamics redirect mRNA location, protein synthesis, and intercalated disc structure to promote cardiomyocyte thickening or elongation, which positions microtubules as upstream effectors of directional growth. Our results identify tunable targets to direct cardiac growth, opening avenues of investigation into cardiac adaptation and disease. Microtubules coordinate directional cardiac remodeling.: Microtubule stabilization redirects nuclear mRNA export and protein synthesis while reinforcing the intercalated disc, promoting cardiomyocyte widening and heart wall thickening (top). Microtubule destabilization disrupts the intercalated disc, allowing cardiomyocyte lengthening and chamber dilation (bottom). [ABSTRACT FROM AUTHOR] |
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| Database: | Psychology and Behavioral Sciences Collection |
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| Abstract: | The adult heart grows by the addition of sarcomeres along the length or width of individual cardiomyocytes, yet how directional growth is spatially coordinated remains unclear. We found that microtubule dynamics could act as a toggle to direct cardiomyocyte growth. Increasing microtubule stability drove cellular widening, concomitant with redirecting messenger RNA (mRNA) export and translation along the width of the cell and reinforcement of the intercalated disc. Conversely, decreasing microtubule stability promoted cellular lengthening, disrupting the intercalated disc and biasing translation and incorporation of new sarcomeric protein toward this structure. Notably, disrupting intercalated disc adhesion was sufficient for cardiomyocyte elongation yet dispensable for cardiomyocyte widening. Thus, the heart coordinates local translation and structural remodeling to orchestrate bidirectional growth. Editor's summary: To adapt to stress, heart walls can thicken or thin, a process driven by the thickening or lengthening of heart muscle cells. However, how muscle cells choose a direction of growth has remained unclear. Scarborough et al. identified microtubule dynamics as a molecular toggle that directs cardiac growth. Stabilizing microtubules redirected RNA export and protein synthesis toward augmenting the cells' width, whereas reinforcing cell-cell junctions promoted cellular thickening. Destabilizing microtubules had the opposite effect, weakening these junctions and permitting cellular elongation. Thus, microtubules direct cardiac geometry by coupling the location of protein synthesis with the remodeling of cell-cell contacts. —Stella M. Hurtley INTRODUCTION: The heart adapts to stress by altering the thickness and geometry of the myocardial walls. This organ-level remodeling is driven primarily by the growth of individual heart muscle cells, or cardiomyocytes. Cardiomyocytes can add contractile units along their width or length to promote wall thickening or thinning—known as concentric and eccentric remodeling, respectively. Growth along these different axes produces fundamentally distinct functional adaptations and pathological consequences, yet the molecular mechanisms that spatially coordinate cardiac growth have remained unclear. RATIONALE: Microtubules are dynamic cytoskeletal filaments that organize intracellular transport, RNA localization, and protein synthesis and are required for generalized cardiac growth. Bidirectional alterations in microtubule stability have been linked to distinct patterns of cardiac remodeling, but whether microtubules actively direct growth, and through which mechanisms, remains unknown. Disparate findings have implicated restructuring of cell-cell contacts at the intercalated disc to eccentric remodeling in mouse and patient tissues. We thus hypothesized that microtubule dynamics may act as a molecular toggle to direct cardiomyocyte thickening or elongation, perhaps in part through structural remodeling of the intercalated disc. RESULTS: Using primary cardiomyocytes and animal models with pharmacologic and genetic manipulation of microtubule dynamics, we found that microtubule stability controlled the direction of cardiac growth through at least two primary mechanisms. In vitro, we found that stabilizing microtubules increased cardiomyocyte width, whereas microtubule destabilization caused cellular lengthening. Mechanistically, microtubule stabilization shifted mRNA export to the nuclear short axis to redirect mRNA and protein synthesis along the width of the cell—a process dependent on the interaction between microtubules and nuclear envelope proteins. Furthermore, microtubule stabilization rapidly reinforced the intercalated disc, whereas microtubule destabilization led to a loss of intercalated disc structure. Disrupting intercalated disc adhesion was sufficient to cause cardiomyocyte elongation and biased the incorporation of newly synthesized contractile proteins toward the cell ends. In vivo, mouse models of cardiac remodeling with increased microtubule stability exhibited relocalized translation and compact intercalated discs with heart wall thickening, whereas microtubule destabilization led to weakening of the intercalated disc and heart wall thinning. Human heart samples mirrored these patterns, where intercalated disc compaction correlated with cardiomyocyte elongation, heart chamber dilation, and worsening cardiac function. CONCLUSION: We propose a model of bidirectional cardiac hypertrophy mediated by the microtubule cytoskeleton. Altered microtubule dynamics redirect mRNA location, protein synthesis, and intercalated disc structure to promote cardiomyocyte thickening or elongation, which positions microtubules as upstream effectors of directional growth. Our results identify tunable targets to direct cardiac growth, opening avenues of investigation into cardiac adaptation and disease. Microtubules coordinate directional cardiac remodeling.: Microtubule stabilization redirects nuclear mRNA export and protein synthesis while reinforcing the intercalated disc, promoting cardiomyocyte widening and heart wall thickening (top). Microtubule destabilization disrupts the intercalated disc, allowing cardiomyocyte lengthening and chamber dilation (bottom). [ABSTRACT FROM AUTHOR] |
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| ISSN: | 00368075 |
| DOI: | 10.1126/science.adz1970 |
