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J. Biol. Chem., Vol. 278, Issue 15, 13367-13375, April 11, 2003

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Targeted Disruption of the ATP2A1 Gene Encoding the Sarco(endo)plasmic Reticulum Ca²⁺ ATPase Isoform 1 (SERCA1) Impairs Diaphragm Function and Is Lethal in Neonatal Mice^*

Yan Pan^§, Elena Zvaritch, A. Russ Tupling^§, William J. Rice, Stella de Leon, Michael Rudnicki^¶, Colin McKerlie^**, Brenda L. Banwell, and David H. MacLennan^§§

From the  Banting and Best Department of Medical Research, University of Toronto, Toronto, Ontario M5G 1L6, Canada, ^¶ Ottawa Health Research Institute, Ottawa, Ontario K1H 8L6, Canada,  Division of Pathology, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada, ^** Department of Laboratory Medicine and Pathobiology, University of Toronto, Banting Institute, Toronto, Ontario M5G 1L5, Canada, and  Department of Pediatrics (Neurology), Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada

Mutations in the ATP2A1 gene, encoding isoform 1 of the sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA1), are one cause of Brody disease, characterized in humans by exercise-induced contraction of fast twitch (type II) skeletal muscle fibers. In an attempt to create a model for Brody disease, the mouse ATP2A1 gene was targeted to generate a SERCA1-null mutant mouse line. In contrast to humans, term SERCA1-null mice had progressive cyanosis and gasping respiration and succumbed from respiratory failure shortly after birth. The percentage of affected homozygote SERCA1^/ mice was consistent with predicted Mendelian inheritance. A survey of multiple organs from 10-, 15-, and 18-day embryos revealed no morphological abnormalities, but analysis of the lungs in term mice revealed diffuse congestion and epithelial hypercellularity and studies of the diaphragm muscle revealed prominent hypercontracted regions in scattered fibers and increased fiber size variability. The V_max of Ca²⁺ transport activity in mutant diaphragm and skeletal muscle was reduced by 80% compared with wild-type muscle, and the contractile response to electrical stimulation under physiological conditions was reduced dramatically in mutant diaphragm muscle. No compensatory responses were detected in analysis of mRNAs encoding other Ca²⁺ handling proteins or of protein levels. Expression of ATP2A1 is largely restricted to type II fibers, which predominate in normal mouse diaphragm. The absence of SERCA1 in type II fibers, and the absence of compensatory increases in other Ca²⁺ handling proteins, coupled with the marked increase in contractile function required of the diaphragm muscle to support postnatal respiration, can account for respiratory failure in term SERCA1-null mice.

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