Skeletal muscle hypertrophy and regeneration are important adaptive responses to both physical activity and pathological stimuli. Failure to maintain these processes underlies the loss of skeletal ...muscle mass and strength that occurs with ageing and in myopathies. Here we show that stable expression of a gene encoding insulin-like growth factor 1 (IGF-1) in C2C12 skeletal muscle cells, or treatment of these cells with recombinant IGF-1 or with insulin and dexamethasone, results in hypertrophy of differentiated myotubes and a switch to glycolytic metabolism. Treatment with IGF-1 or insulin and dexamethasone mobilizes intracellular calcium, activates the Ca2+/calmodulin-dependent phosphatase calcineurin, and induces the nuclear translocation of the transcription factor NF-ATc1. Hypertrophy is suppressed by the calcineurin inhibitors cyclosporin A or FK506, but not by inhibitors of the MAP-kinase or phosphatidylinositol-3-OH kinase pathways. Injecting rat latissimus dorsi muscle with a plasmid encoding IGF-1 also activates calcineurin, mobilizes satellite cells and causes a switch to glycolytic metabolism. We propose that growth-factor-induced skeletal-muscle hypertrophy and changes in myofibre phenotype are mediated by calcium mobilization and are critically regulated by the calcineurin/NF-ATc1 signalling pathway.
Abstract Purpose Variants in MYBPC3 causing loss-of-function are the most common cause of HCM. However, a substantial number of patients carry missense variants of uncertain significance (VUS) in ...MYBPC3. We hypothesize that a structural-based algorithm, STRUM, which estimates the effect of missense variants on protein folding, will improve clinical risk stratification of patients with HCM and a MYBPC3 VUS. Methods Among 7,963 patients in the multi-center Sarcomeric Human Cardiomyopathy Registry, 120 unique missense VUSs in MYBPC3 were identified. Variants were evaluated for their effect on subdomain folding and a stratified time-to-event analysis for an overall composite endpoint (first occurrence of ventricular arrhythmia, heart failure, all-cause mortality, atrial fibrillation, and stroke) was performed for patients with HCM and a MYBPC3 missense VUS. Results We demonstrated that patients carrying a MYBPC3 VUS predicted to cause subdomain misfolding (STRUM +, ΔΔG ≤-1.2 kcal/mol) exhibited a higher rate of adverse events compared to those with a STRUM-VUS (Hazard Ratio=2.29, P=0.0282). In silico saturation mutagenesis of MYBPC3 identified 4,943/23,427 (21%) missense variants that were predicted to cause subdomain misfolding. Conclusions STRUM enables clinical risk stratification of patients with HCM and a MYBPC3 VUS and has the capacity to improve prognostic predictions and clinical decision making. Competing Interest Statement Funding for SHaRe has been provided by an unrestricted research grant by Myokardia, Inc a startup company that is developing therapeutics that target the sarcomere. Myokardia, Inc had no role in the preparation of this manuscript or approving the content of this manuscript. Drs. Helms, Ho, Day, Saberi, Olivotto, Colan, Ingles and Ashley receive research support from MyoKardia, Inc. Dr. Thompson receives compensation as an editor for Merck Manuals. Research funding for all authors is detailed within the acknowledgement sections of this manuscript. The other authors report no relevant conflicts of interest.
Hypertrophic cardiomyopathy (HCM) was the first cardiovascular disorder in which a genetic basis was identified. The disease is characterized by a marked thickening of the left ventricle and is the ...most common structural cause of sudden cardiac death in those aged under 35 years. HCM is primarily a disease of the sarcomere with over 250 mutations identified currently within 13 sarcomere-related genes. At present, genetic screening is available for the genes shown to cause HCM most frequently, with a mutation pick-up rate of up to 60%. Current research is focused on the identification of additional causative genes and elucidation into signaling mechanisms involved in HCM pathogenesis, as well as investigation of modifying factors that can alter the clinical phenotype in HCM. The unifying goal of these studies is to improve our understanding of disease pathogenesis in HCM, thereby facilitating the process of new diagnostic and therapeutic approaches in patients, ultimately leading to disease prevention and possible curative treatment.
Cardiovascular Genetics Semsarian, Christopher; Seidman, Christine
Principles of Molecular Cardiology
Book Chapter
When the double helical structure of DNA was first proposed in 1953 by Watson and Crick in a two-page Nature article (1), no one could have predicted the tremendous impact this discovery would have ...in establishing the study of human genetic diseases. This discovery was an important landmark in the development of the field of cardiovascular genetics. In the last 30 years, several technological advances have fueled a surge in cardiovascular genetic research. Such advances include the understanding of biochemical components of DNA, the development of cloning techniques and DNA sequencing, the amplification of DNA by polymerase chain reaction (PCR), the identification of restriction enzymes (the molecular biologist’s “scalpel”) for handling small pieces of DNA, and the undertaking of the Human Genome Project (2). Today, cardiovascular genetics is characterized by the integration of high-technology laboratory studies and clinical medicine. Within the last decade, cardiovascular genetics has redefined the etiology and diagnostic criteria for numerous diseases and has led to the development of new, individualized treatment for cardiovascular diseases.
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