Increased susceptibility to isoproterenol-induced cardiac hypertrophy and impaired weight gain in mice lacking the histidine-rich calcium-binding protein.
The sarcoplasmic reticulum (SR) plays a critical role in excitation-contraction coupling by regulating the cytoplasmic calcium concentration of striated muscle. The histidine-rich calcium-binding protein (HRCBP) is expressed in the junctional SR, the site of calcium release from the SR. HRCBP is expressed exclusively in muscle tissues and binds calcium with low affinity and high capacity. In addition, HRCBP interacts with triadin, a protein associated with the ryanodine receptor and thought to be involved in calcium release. Its calcium binding properties, localization to the SR, and interaction with triadin suggest that HRCBP is involved in calcium handling by the SR. To determine the function of HRCBP in vivo, we inactivated HRC, the gene encoding HRCBP, in mice. HRC knockout mice exhibited impaired weight gain beginning at 11 months of age, which was marked by reduced skeletal muscle and fat mass, and triadin protein expression was upregulated in the heart of HRC knockout mice. In addition, HRC null mice displayed a significantly exaggerated response to the induction of cardiac hypertrophy by isoproterenol compared to their wild-type littermates. The exaggerated response of HRC knockout mice to the induction of cardiac hypertrophy is consistent with a regulatory role for HRCBP in calcium handling in vivo and suggests that mutations in HRC, in combination with other genetic or environmental factors, might contribute to pathological hypertrophy and heart failure.
Jaehnig
Eric J
EJ
Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143-2240, USA.
Heidt
Analeah B
AB
Greene
Stephanie B
SB
Cornelissen
Ivo
I
Black
Brian L
BL
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D020022:Genetic Predisposition to Disease; D007545:Isoproterenol; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism; D015430:Weight Gain / Q000235:genetics*
D002135:Calcium-Binding Proteins; C489418:Hrc protein, mouse; D009124:Muscle Proteins; D007545:Isoproterenol; D002118:Calcium