Loss of skeletal muscle strength by ablation of the sarcoplasmic reticulum protein JP45

doi:10.1073/pnas.0707389104

Loss of skeletal muscle strength by ablation of the sarcoplasmic reticulum protein JP45

^†Departments of Anaesthesia and Research, Basel University Hospital, Hebelstrasse 20, 4031 Basel, Switzerland;
*Departments of Physiology, Pharmacology, and Internal Medicine; Gerontology; and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157;
^‡Santhera Pharmaceuticals, CH-4410 Liestal, Switzerland;
^§Department of Biological Chemistry, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan; and
^¶Department of Experimental and Diagnostic Medicine, General Pathology Section, University of Ferrara, Via Borsari 46, 44100 Ferrara, Italy

Edited by Andrew R. Marks, Columbia University College of Physicians and Surgeons, New York, NY, and approved October 24, 2007 (received for review August 6, 2007)

Abstract

Skeletal muscle constitutes ≈40% of the human body mass, and alterations in muscle mass and strength may result in physical disability. Therefore, the elucidation of the factors responsible for muscle force development is of paramount importance. Excitation–contraction coupling (ECC) is a process during which the skeletal muscle surface membrane is depolarized, causing a transient release of calcium from the sarcoplasmic reticulum that activates the contractile proteins. The ECC machinery is complex, and the functional role of many of its protein components remains elusive. This study demonstrates that deletion of the gene encoding the sarcoplasmic reticulum protein JP45 results in decreased muscle strength in young mice. Specifically, this loss of muscle strength in JP45 knockout mice is caused by decreased functional expression of the voltage-dependent Ca²⁺ channel Ca_v1.1, which is the molecule that couples membrane depolarization and calcium release from the sarcoplasmic reticulum. These results point to JP45 as one of the molecules involved in the development or maintenance of skeletal muscle strength.

Footnotes

^‖To whom correspondence should be addressed. E-mail: zor{at}unife.it
Author contributions: O.D., H.T., and F.Z. designed research; O.D., J.X., S.T., Z.-M.W., R.J.-M., A.M.P., M.L.M., M.N., H.T., and F.Z. performed research; F.S. contributed new reagents/analytic tools; O.D., J.X., S.T., Z.-M.W., R.J.-M., A.M.P., M.L.M., A.B., and F.Z. analyzed data; and O.D., S.T., and F.Z. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0707389104/DC1.