Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disease characterized by an increase in left ventricular wall mass in the absence of another cause for hypertrophy. Because hypertrophy is a fundamental response of the heart and may be both adaptive and maladaptive, the study of HCM provides a window to an important physiologic cardiac process. Approximately 15% of cases are the results of a mutation in the beta myosin heavy chain (BMHC), a dominant protein in the thick filaments of muscle fibers. We have identified 32 mutations in the BMHC gene and have described their distribution on the 3-dimensional structure of myosin as solved by Rayment et al. Their clustering into 4 regions have suggested that they may interfere with the acto-myosin crossbridge interaction in different portions of the cycle, thus leading to inefficient molecular motors with different structural and functional defects. Recently we have found that distinct mutations in either of the myosin light chains which bind to heavy myosin can cause a rare cardiac and skeletal myopathy. Functional analysis of these myosins are abnormal in a way that differs from the mutant heavy chains previously evaluated. The distribution of the light chain mutations and the associated cardiac phenotype has prompted us to hypothesize that they disrupt the stretch-activation response in the heart. This intrinsic property of some muscle is the basis of insect flight. We have produced a trans-genic mouse with one of these human mutant light chains. The cardiac muscle of these mice will allow us to test the impact of these mutations on stretch-activation and provide a substrate for therapeutic interventions. The physiologic analysis of muscle fibers containing the light chain mutations will allow us to study what we believe is a basic property of heart muscle that has not been adequately characterized. Should this property prove to be physiologically essential to cardiac function, it may be possible to improve cardiac failure through interventions that modify the stretch-activation response.