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Structural and functional diversity of human ventricular myosin
Insights
Subcellular alterations in heart muscle, specifically myosin, are key to heart failure. A new myosin heterogeneity (VA/VB ratio) is influenced by hemodynamic load, offering potential therapeutic targets.
Area of Science:
- Cardiology
- Molecular Biology
- Biochemistry
Background:
- Subcellular alterations' role in heart failure is unclear.
- Contractile dysfunction in heart failure may involve myosin alterations.
- Myofibrillar and myosin ATPase activity changes in heart failure are debated.
Purpose of the Study:
- Investigate myosin heterogeneity in heart failure.
- Determine the cause of reduced myosin ATPase activity.
- Explore the diagnostic and therapeutic potential of myosin heterogeneity.
Main Methods:
- Optimized native polyacrylamide gel electrophoresis with pyrophosphate.
- Analyzed ventricular myosin from patients and normal hearts.
- Correlated myosin heterogeneity with hemodynamic load in surgical specimens.
Main Results:
- Identified two myosin bands (VA and VB) in ventricles.
- VA/VB heterogeneity exists in normal hearts, not specific to disease.
- The VA/VB ratio increased with diastolic and systolic load in surgical samples.
Conclusions:
- Myosin heterogeneity (VA/VB) is influenced by hemodynamic load.
- This heterogeneity may be susceptible to post-mortem modification.
- Further research is needed to understand the molecular basis and therapeutic potential of VA/VB ratio.
Abstract:
The role of subcellular alterations in the process of heart failure remains ill-defined. Because contractile performance of failing heart muscle is depressed, possible alterations in the myosin molecule could be of particular relevance. There is increasing evidence that myofibrillar ATPase activity is reduced in congestive heart failure, whereas the findings on myosin ATPase are still controversial. The molecular causes of the reduced activity are currently not known. Because alpha-MHC is present only in small amounts in normal ventricles, a shift in favor of beta-MHC is of minor importance. Also immunohistochemical data on subspecies of beta-MHC seem not to provide an explanation. A new type of myosin heterogeneity was found by optimizing native polyacrylamide gel electrophoresis in the presence of pyrophosphate. Two bands (VA and VB) were observed in ventricles of patients with valvular disease. Because the two bands were detected also in normal hearts of large mammals, the existence of VA/VB cannot be diagnostic of diseased heart. However, the VA/VB ratio was influenced by the hemodynamic load, whereby the fast migrating band (VA) increased with the diastolic and systolic load. Because a relationship with the hemodynamic load was observed only in surgical muscle specimens, it appears that this heterogeneity is prone to post mortem modification. Further work is required to identify the molecular nature of this heterogeneity and to examine the therapeutic potential of a pharmacological modification of the VA/VB ratio.