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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
Hypothesis and theory: mechanical instabilities and non-uniformities in hereditary sarcomere myopathies
1Department of Chemistry and Biomedical Sciences, Linnaeus University Kalmar, Sweden.
Insights
Familial hypertrophic cardiomyopathy (HCM) arises from sarcomere protein mutations, leading to heart dysfunction and sudden death. This study explores how these mutations may cause cellular mechanical instabilities, driving long-term cardiac remodeling and disease progression.
Area of Science:
- Cardiovascular Biology
- Muscle Physiology
- Genetic Diseases
Background:
- Familial hypertrophic cardiomyopathy (HCM) is a genetic disorder affecting 1/500 individuals, often causing sudden death.
- Mutations in sarcomere protein genes, like MYH7, are implicated in both cardiac and skeletal muscle diseases.
- The precise mechanisms linking moderate mutation-induced protein dysfunction to long-term cardiac remodeling and fibrosis remain unclear.
Purpose of the Study:
- To investigate potential mechanisms by which sarcomere protein mutations cause cellular mechanical instabilities.
- To explore how these instabilities might initiate secondary remodeling, hypertrophy, and fibrosis in the heart.
- To consider the applicability of these mechanisms to skeletal muscle and discuss species-specific differences.
Main Methods:
- Theoretical consideration of cellular mechanics in mutated sarcomeres.
- Modeling studies to illustrate proposed mechanisms of contractile instability and altered tension generation.
- Proposal of experimental tests to validate the proposed mechanisms.
Main Results:
- Mutated sarcomere proteins may induce contractile instabilities and differential tension generation within cardiac cells.
- These cellular mechanical alterations could act as initiating stimuli for hypertrophic remodeling and fibrosis.
- Similar mechanisms may apply to skeletal muscle, with distinct outcomes due to tissue-specific differences.
Conclusions:
- Cellular mechanical instabilities, arising from sarcomere protein mutations, offer a plausible explanation for the long-term pathological remodeling in HCM.
- These findings provide a framework for understanding the pathogenesis of HCM and related muscle disorders.
- Further experimental validation is needed to confirm these proposed mechanisms in both cardiac and skeletal muscle.
Abstract:
Familial hypertrophic cardiomyopathy (HCM), due to point mutations in genes for sarcomere proteins such as myosin, occurs in 1/500 people and is the most common cause of sudden death in young individuals. Similar mutations in skeletal muscle, e.g., in the MYH7 gene for slow myosin found in both the cardiac ventricle and slow skeletal muscle, may also cause severe disease but the severity and the morphological changes are often different. In HCM, the modified protein function leads, over years to decades, to secondary remodeling with substantial morphological changes, such as hypertrophy, myofibrillar disarray, and extensive fibrosis associated with severe functional deterioration. Despite intense studies, it is unclear how the moderate mutation-induced changes in protein function cause the long-term effects. In hypertrophy of the heart due to pressure overload (e.g., hypertension), mechanical stress in the myocyte is believed to be major initiating stimulus for activation of relevant cell signaling cascades. Here it is considered how expression of mutated proteins, such as myosin or regulatory proteins, could have similar consequences through one or both of the following mechanisms: (1) contractile instabilities within each sarcomere (with more than one stable velocity for a given load), (2) different tension generating capacities of cells in series. These mechanisms would have the potential to cause increased tension and/or stretch of certain cells during parts of the cardiac cycle. Modeling studies are used to illustrate these ideas and experimental tests are proposed. The applicability of similar ideas to skeletal muscle is also postulated, and differences between heart and skeletal muscle are discussed.
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