Elevated Ca2+ transients and increased myofibrillar power generation cause cardiac hypercontractility in a model of Noonan syndrome with multiple lentigines.
Noonan syndrome with multiple lentigines (NSML) is primarily caused by mutations in the nonreceptor protein tyrosine phosphatase SHP2 and associated with congenital heart disease in the form of pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM). Our goal was to elucidate the cellular mechanisms underlying the development of HCM caused by the Q510E mutation in SHP2. NSML patients carrying this mutation suffer from a particularly severe form of HCM. Drawing parallels to other, more common forms of HCM, we hypothesized that altered Ca(2+) homeostasis and/or sarcomeric mechanical properties play key roles in the pathomechanism. We used transgenic mice with cardiomyocyte-specific expression of Q510E-SHP2 starting before birth. Mice develop neonatal onset HCM with increased ejection fraction and fractional shortening at 4-6 wk of age. To assess Ca(2+) handling, isolated cardiomyocytes were loaded with fluo-4. Q510E-SHP2 expression increased Ca(2+) transient amplitudes during excitation-contraction coupling and increased sarcoplasmic reticulum Ca(2+) content concurrent with increased expression of sarco(endo)plasmic reticulum Ca(2+)-ATPase. In skinned cardiomyocyte preparations from Q510E-SHP2 mice, force-velocity relationships and power-load curves were shifted upward. The peak power-generating capacity was increased approximately twofold. Transmission electron microscopy revealed that the relative intracellular area occupied by sarcomeres was increased in Q510E-SHP2 cardiomyocytes. Triton X-100-based myofiber purification showed that Q510E-SHP2 increased the amount of sarcomeric proteins assembled into myofibers. In summary, Q510E-SHP2 expression leads to enhanced contractile performance early in disease progression by augmenting intracellular Ca(2+) cycling and increasing the number of power-generating sarcomeres. This gives important new insights into the cellular pathomechanisms of Q510E-SHP2-associated HCM.
Department of Medical Pharmacology and Physiology/Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri.
Sarah A
SA
Clay
Department of Medical Pharmacology and Physiology/Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri.
Timothy L
TL
Domeier
Department of Medical Pharmacology and Physiology/Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri.
Laurin M
LM
Hanft
Department of Medical Pharmacology and Physiology/Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri.
Kerry S
KS
McDonald
Department of Medical Pharmacology and Physiology/Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri krenzm@missouri.edu.
Maike
M
Krenz
D000818:Animals; D020013:Calcium Signaling; D004195:Disease Models, Animal; D056966:Excitation Contraction Coupling; D005260:Female; D005838:Genotype; D044542:LEOPARD Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008822:Mice, Transgenic; D053580:Muscle Strength; D009154:Mutation; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000648:ultrastructure; D010641:Phenotype; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism; D012518:Sarcomeres / Q000378:metabolism* / Q000648:ultrastructure; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D013318:Stroke Volume
D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
cardiac hypertrophy; contractility; protein tyrosine phosphatase; sarco(endo)plasmic reticulum Ca2+-ATPase; sarcomeric function