Impaired Ca2+ Store Functions in Skeletal and Cardiac Muscle Cells from Sarcalumenin-deficient Mice

Shinji Komazaki,Miei Shimura,Miyuki Nishi,Hideaki Kume,Teruyuki Yanagisawa,Yasutake Saeki,Kiyoyuki Matsumura,Hiroshi Takeshima,Morikatsu Yoshida,Yoshihiro Ishikawa,Minori Saito,Miao Zhang,Susumu Minamisawa

doi:10.1074/jbc.m406618200

Abstract

Sarcalumenin (SAR), specifically expressed in striated muscle cells, is a Ca2+-binding protein localized in the sarcoplasmic reticulum (SR) of the intracellular Ca2+ store. By generating SAR-deficient mice, we herein examined its physiological role. The mutant mice were apparently normal in growth, health, and reproduction, indicating that SAR is not essential for fundamental muscle functions. SAR-deficient skeletal muscle carrying irregular SR ultrastructures retained normal force generation but showed slow relaxation phases after contractions. A weakened Ca2+ uptake activity was detected in the SR prepared from mutant muscle, indicating that SAR contributes to Ca2+ buffering in the SR lumen and also to the maintenance of Ca2+ pump proteins. Cardiac myocytes from SAR-deficient mice showed slow contraction and relaxation accompanied by impaired Ca2+ transients, and the mutant mice exhibited a number of impairments in cardiac performance as determined in electrocardiography, ventricular catheterization, and echocardiography. The results obtained demonstrate that SAR plays important roles in improving the Ca2+ handling functions of the SR in striated muscle.

Highlights

Sarcalumenin (SAR), expressed in striated muscle cells, is a Ca2؉-binding protein localized in the sarcoplasmic reticulum (SR) of the intracellular Ca2؉ store
Between mouse and rabbit SAR primary structures, high conservation is observed in the carboxyl-terminal region, whereas moderate divergence is observed in the amino-terminal half (Fig. 1D)
The irregular SR structures are impressive in SAR-deficient skeletal muscle (Fig. 2)

Summary

Introduction

Sarcalumenin (SAR), expressed in striated muscle cells, is a Ca2؉-binding protein localized in the sarcoplasmic reticulum (SR) of the intracellular Ca2؉ store. Our search of the NCBI data base found putative nucleotide-binding motifs for the P-loopcontaining ATPase/GTPase in the carboxyl-terminal region shared by SAR isoforms (see Fig. 1). This observation may suggest that SAR has an enzyme activity in the SR lumen in addition to its role in Ca2ϩ buffering. By generating and analyzing a mouse model carrying the targeted mutation, we determine the important contribution of SAR to SR functions in skeletal and cardiac muscle cells

Methods

Results

Conclusion