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Ex vivo stretch reveals altered mechanical properties of isolated dystrophin-deficient hearts.

Barnabei MS, Metzger JM - PLoS ONE (2012)

Bottom Line: Previous reports have shown that loss of dystrophin causes sarcolemmal instability and reduced mechanical compliance of isolated cardiac myocytes.During LV chamber distention, sarcomere lengths increased similarly in mdx and WT hearts despite greater excursions in volume of mdx hearts.In comparison, similar increases in LV compliance were obtained in isolated hearts from β-sarcoglycan- and laminin-α(2) mutant mice, but not in dysferlin- mice, suggesting that increased whole-organ compliance in mdx mice is a specific effect of disrupted cell-extracellular matrix contacts and not a general consequence of cardiomyopathy via membrane defect processes.

View Article: PubMed Central - PubMed

Affiliation: Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.

ABSTRACT
Duchenne muscular dystrophy (DMD) is a progressive and fatal disease of muscle wasting caused by loss of the cytoskeletal protein dystrophin. In the heart, DMD results in progressive cardiomyopathy and dilation of the left ventricle through mechanisms that are not fully understood. Previous reports have shown that loss of dystrophin causes sarcolemmal instability and reduced mechanical compliance of isolated cardiac myocytes. To expand upon these findings, here we have subjected the left ventricles of dystrophin-deficient mdx hearts to mechanical stretch. Unexpectedly, isolated mdx hearts showed increased left ventricular (LV) compliance compared to controls during stretch as LV volume was increased above normal end diastolic volume. During LV chamber distention, sarcomere lengths increased similarly in mdx and WT hearts despite greater excursions in volume of mdx hearts. This suggests that the mechanical properties of the intact heart cannot be modeled as a simple extrapolation of findings in single cardiac myocytes. To explain these findings, a model is proposed in which disruption of the dystrophin-glycoprotein complex perturbs cell-extracellular matrix contacts and promotes the apparent slippage of myocytes past each other during LV distension. In comparison, similar increases in LV compliance were obtained in isolated hearts from β-sarcoglycan- and laminin-α(2) mutant mice, but not in dysferlin- mice, suggesting that increased whole-organ compliance in mdx mice is a specific effect of disrupted cell-extracellular matrix contacts and not a general consequence of cardiomyopathy via membrane defect processes. Collectively, these findings suggest a novel and cell-death independent mechanism for the progressive pathological LV dilation that occurs in DMD.

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Simplified model for the mechanical properties of the dystrophic myocardium.Top, model for the increased stiffness of mdx myocytes. Stretch causes membrane permeability and influx of extracellular calcium, leading to unregulated contraction (indicated in red). Bottom, simplified model for the effects of dystrophin expression on myocardial compliance. In mdx hearts, membrane permeability may initially cause contraction of LV volume at normal LVEDP, resulting in a left shift in the LV volume-EDP curve. As volume is increased, loss of dystrophin leads to increased slippage of myocytes past one another, leading to increased compliance. This is corrected by expression of dystrophin in 50% of myocytes in mdx carrier females.
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pone-0032880-g005: Simplified model for the mechanical properties of the dystrophic myocardium.Top, model for the increased stiffness of mdx myocytes. Stretch causes membrane permeability and influx of extracellular calcium, leading to unregulated contraction (indicated in red). Bottom, simplified model for the effects of dystrophin expression on myocardial compliance. In mdx hearts, membrane permeability may initially cause contraction of LV volume at normal LVEDP, resulting in a left shift in the LV volume-EDP curve. As volume is increased, loss of dystrophin leads to increased slippage of myocytes past one another, leading to increased compliance. This is corrected by expression of dystrophin in 50% of myocytes in mdx carrier females.

Mentions: To determine the effects of whole-organ stretch on individual myocytes in WT and mdx hearts, we determined sarcomere length at a given LV pressure in non-contracting hearts. Sarcomere lengths were similar at all LV pressures tested despite the considerably larger volumes required to alter LV volume in mdx hearts, suggesting that enhanced stretch of the myocytes does not account for increased compliance in isolated mdx hearts. Since alterations in LV volume expansion are not strictly tracked by proportional changes in sarcomere length, this indicates the mechanical properties of the dystrophic myocardium are not a simple extrapolation of findings from isolated cells. To explain these findings, we propose a model for the accelerated pathological dilation of the ventricle in DMD where disruption of the DGC promotes side-to-side myocyte slippage during whole-organ stretch. A simplified model for this mechanism is shown in Figure 5. Specifically, we propose that as isolated mdx hearts are stretched, loss of dystrophin and disruption of the DGC causes myocytes to translate past each other to a greater degree than occurs in normal hearts. We speculate that, over time, this enhanced myocyte slippage contribute to the pathological dilation of the heart observed in DMD and other forms of inherited muscular dystrophy which involve disruption of cell-extracellular matrix linkages. Therefore, in this model, enhanced compliance in mdx isolated hearts is primarily due to disruptions in the cytoskeleton-DGC-extracellular matrix axis. Additional experiments showed similarly enhanced compliance in β-sarcoglycan- and dy2J hearts, but not in dysferlin- hearts, consistent with our hypothesis that disruption of the DGC-mediated linkage of cells with the extracellular matrix promotes enhanced whole-organ cardiac compliance. Collectively, these findings support a mechanism for the increased whole-organ compliance of mdx isolated hearts which is independent of sarcolemma instability and single myocyte compliance. In the broader context of pathophysiological processes associated in DMD cardiomyopathy, the findings presented here suggest a novel mechanism for the pathological ventricular dilation that occurs in DMD and highlight the complex physiological interactions that should be considered when studying diseases at the whole-organ level.


Ex vivo stretch reveals altered mechanical properties of isolated dystrophin-deficient hearts.

Barnabei MS, Metzger JM - PLoS ONE (2012)

Simplified model for the mechanical properties of the dystrophic myocardium.Top, model for the increased stiffness of mdx myocytes. Stretch causes membrane permeability and influx of extracellular calcium, leading to unregulated contraction (indicated in red). Bottom, simplified model for the effects of dystrophin expression on myocardial compliance. In mdx hearts, membrane permeability may initially cause contraction of LV volume at normal LVEDP, resulting in a left shift in the LV volume-EDP curve. As volume is increased, loss of dystrophin leads to increased slippage of myocytes past one another, leading to increased compliance. This is corrected by expression of dystrophin in 50% of myocytes in mdx carrier females.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3298453&req=5

pone-0032880-g005: Simplified model for the mechanical properties of the dystrophic myocardium.Top, model for the increased stiffness of mdx myocytes. Stretch causes membrane permeability and influx of extracellular calcium, leading to unregulated contraction (indicated in red). Bottom, simplified model for the effects of dystrophin expression on myocardial compliance. In mdx hearts, membrane permeability may initially cause contraction of LV volume at normal LVEDP, resulting in a left shift in the LV volume-EDP curve. As volume is increased, loss of dystrophin leads to increased slippage of myocytes past one another, leading to increased compliance. This is corrected by expression of dystrophin in 50% of myocytes in mdx carrier females.
Mentions: To determine the effects of whole-organ stretch on individual myocytes in WT and mdx hearts, we determined sarcomere length at a given LV pressure in non-contracting hearts. Sarcomere lengths were similar at all LV pressures tested despite the considerably larger volumes required to alter LV volume in mdx hearts, suggesting that enhanced stretch of the myocytes does not account for increased compliance in isolated mdx hearts. Since alterations in LV volume expansion are not strictly tracked by proportional changes in sarcomere length, this indicates the mechanical properties of the dystrophic myocardium are not a simple extrapolation of findings from isolated cells. To explain these findings, we propose a model for the accelerated pathological dilation of the ventricle in DMD where disruption of the DGC promotes side-to-side myocyte slippage during whole-organ stretch. A simplified model for this mechanism is shown in Figure 5. Specifically, we propose that as isolated mdx hearts are stretched, loss of dystrophin and disruption of the DGC causes myocytes to translate past each other to a greater degree than occurs in normal hearts. We speculate that, over time, this enhanced myocyte slippage contribute to the pathological dilation of the heart observed in DMD and other forms of inherited muscular dystrophy which involve disruption of cell-extracellular matrix linkages. Therefore, in this model, enhanced compliance in mdx isolated hearts is primarily due to disruptions in the cytoskeleton-DGC-extracellular matrix axis. Additional experiments showed similarly enhanced compliance in β-sarcoglycan- and dy2J hearts, but not in dysferlin- hearts, consistent with our hypothesis that disruption of the DGC-mediated linkage of cells with the extracellular matrix promotes enhanced whole-organ cardiac compliance. Collectively, these findings support a mechanism for the increased whole-organ compliance of mdx isolated hearts which is independent of sarcolemma instability and single myocyte compliance. In the broader context of pathophysiological processes associated in DMD cardiomyopathy, the findings presented here suggest a novel mechanism for the pathological ventricular dilation that occurs in DMD and highlight the complex physiological interactions that should be considered when studying diseases at the whole-organ level.

Bottom Line: Previous reports have shown that loss of dystrophin causes sarcolemmal instability and reduced mechanical compliance of isolated cardiac myocytes.During LV chamber distention, sarcomere lengths increased similarly in mdx and WT hearts despite greater excursions in volume of mdx hearts.In comparison, similar increases in LV compliance were obtained in isolated hearts from β-sarcoglycan- and laminin-α(2) mutant mice, but not in dysferlin- mice, suggesting that increased whole-organ compliance in mdx mice is a specific effect of disrupted cell-extracellular matrix contacts and not a general consequence of cardiomyopathy via membrane defect processes.

View Article: PubMed Central - PubMed

Affiliation: Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.

ABSTRACT
Duchenne muscular dystrophy (DMD) is a progressive and fatal disease of muscle wasting caused by loss of the cytoskeletal protein dystrophin. In the heart, DMD results in progressive cardiomyopathy and dilation of the left ventricle through mechanisms that are not fully understood. Previous reports have shown that loss of dystrophin causes sarcolemmal instability and reduced mechanical compliance of isolated cardiac myocytes. To expand upon these findings, here we have subjected the left ventricles of dystrophin-deficient mdx hearts to mechanical stretch. Unexpectedly, isolated mdx hearts showed increased left ventricular (LV) compliance compared to controls during stretch as LV volume was increased above normal end diastolic volume. During LV chamber distention, sarcomere lengths increased similarly in mdx and WT hearts despite greater excursions in volume of mdx hearts. This suggests that the mechanical properties of the intact heart cannot be modeled as a simple extrapolation of findings in single cardiac myocytes. To explain these findings, a model is proposed in which disruption of the dystrophin-glycoprotein complex perturbs cell-extracellular matrix contacts and promotes the apparent slippage of myocytes past each other during LV distension. In comparison, similar increases in LV compliance were obtained in isolated hearts from β-sarcoglycan- and laminin-α(2) mutant mice, but not in dysferlin- mice, suggesting that increased whole-organ compliance in mdx mice is a specific effect of disrupted cell-extracellular matrix contacts and not a general consequence of cardiomyopathy via membrane defect processes. Collectively, these findings suggest a novel and cell-death independent mechanism for the progressive pathological LV dilation that occurs in DMD.

Show MeSH
Related in: MedlinePlus