Dystrophin- and MLP-deficient mouse hearts: marked differences in morphology and function, but similar accumulation of cytoskeletal proteins
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Published on: June 14, 2016
James R Wilding1, Jürgen E Schneider, A Elizabeth Sang
1Department of Physiology, University of Oxford, Oxford, England, UK.
Insights
Muscle LIM protein (MLP) deficiency causes dilated cardiomyopathy and heart failure in mice, unlike dystrophin deficiency. Compensatory proteins prevent heart failure in dystrophin-null mice but not in MLP-null mice.
Area of Science:
- Cardiovascular Biology
- Muscle Physiology
- Genetic Disease Models
Background:
- Mutations in cytoskeletal proteins like dystrophin and muscle LIM protein (MLP) are linked to human dilated cardiomyopathy.
- Mouse models may exhibit different cardiac phenotypes due to compensatory protein accumulation.
Purpose of the Study:
- To investigate the distinct effects of dystrophin deficiency and MLP deficiency on left-ventricular (LV) morphology and function in mice.
- To determine the role of compensatory cytoskeletal protein accumulation in mitigating or exacerbating cardiac dysfunction.
Main Methods:
- High-resolution cine-magnetic resonance imaging (MRI) for in vivo LV morphology and function assessment.
- Assessment of LV passive stiffness in isolated, perfused hearts.
- Western blot analysis to quantify cytoskeletal protein levels.
Main Results:
- MLP-null mice exhibited dilated cardiomyopathy with increased LV size and significantly reduced ejection fraction, indicating heart failure.
- Dystrophin-deficient (mdx) mice showed normal LV morphology and function, suggesting compensation.
- Both models showed increased desmin and beta-tubulin; mdx hearts accumulated utrophin and MLP, while MLP-null hearts accumulated dystrophin and syncoilin.
Conclusions:
- The accumulation of MLP and utrophin in mdx mice compensated for dystrophin loss, preventing heart failure.
- Inadequate compensatory protein accumulation (desmin, syncoilin, dystrophin) in MLP-null hearts led to dilated cardiomyopathy and heart failure.
- MLP plays a critical role in maintaining cardiac structure and function, with its loss leading to severe heart failure in mice.
Abstract:
In humans, cytoskeletal dystrophin and muscle LIM protein (MLP) gene mutations can cause dilated cardiomyopathy, yet these mutations may have different effects in mice, owing to increased accumulation of other, compensatory cytoskeletal proteins. Consequently, we characterized left-ventricular (LV) morphology and function in vivo using high-resolution cine-magnetic resonance imaging (MRI) in 2- to 3-month old dystrophin-deficient (mdx) and MLP-null mice, and their respective controls. LV passive stiffness was assessed in isolated, perfused hearts, and cytoskeletal protein levels were determined using Western blot analyses. In mdx mouse hearts, LV-to-body weight ratio, cavity volume, ejection fraction, stroke volume, and cardiac output were normal. However, MLP-null mouse hearts had 1.2-fold higher LV-to-body weight ratios (P<0.01), 1.5-fold higher end-diastolic volumes (P<0.01), and decreased ejection fraction compared with controls (25% vs. 66%, respectively, P<0.01), indicating dilated cardiomyopathy and heart failure. In both models, isolated, perfused heart end-diastolic pressure-volume relationships and passive left-ventricular stiffness were normal. Hearts from both models accumulated desmin and beta-tubulin, mdx mouse hearts accumulated utrophin and MLP, and MLP-null mouse hearts accumulated dystrophin and syncoilin. Although the increase in MLP and utrophin in the mdx mouse heart was able to compensate for the loss of dystrophin, accumulation of desmin, syncoilin and dystrophin were unable to compensate for the loss of MLP, resulting in heart failure.
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