title: Hypothesis and theory: mechanical instabilities and non-uniformities in hereditary sarcomere myopathies.
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.
authors.affiliation: Department of Chemistry and Biomedical Sciences, Linnaeus University Kalmar, Sweden.
authors.forename: Alf
authors.initials: A
authors.lastname: Månsson
keywords: actomyosin; force-velocity relationship; heart; myopathy; skeletal muscle; striated muscle