ARTICLES

Cell Research (2004); 14(5):373-378

Defective maintenance of intracellular Ca²⁺ homeostasis is linked to increased muscle fatigability in the MG29 null mice

Marco A. P. Brotto^1*, Ramakrishnan Y. Nagaraj¹, Leticia S. Brotto¹, Hiroshi Takeshima³,Jianjie Ma¹, Thomas M. Nosek²

¹Department of Physiology and Biophysics, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA;
²Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA;
³Department of Biochemistry, Graduate School of Medicine,Tohoku University 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan

Reseived: Apr 6, 2004    Revised: Jun 28, 2004    Accepted: Jul 10, 2004

Correspondence: Marco A. P. Brotto brottoma@umdnj.edu

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Mitsugumin 29 (MG29) is a transmembrane protein that is normally found in the triad junction of skeletal muscle. Our previous studies have shown that targeted deletion of mg29 from the skeletal muscle resulted in abnormality of the triad junction structure, and also increased susceptibility to muscle fatigue. To elucidate the basis of these effects, we investigated the properties of Ca²⁺-uptake and -release in toxin-skinned Extensor Digitorium Longus (EDL) muscle fibers from control and mg29 knockout mice. Compared with the control muscle, submaximal Ca²⁺-uptake into the sarcoplasmic reticulum (SR) was slower and the storage of Ca²⁺ inside the SR was less in the mutant muscle, due to increased leakage process of Ca²⁺ movement across the SR. The leakage pathway is associated with the increased sensitivity of Ca²⁺/caffeine -induced Ca²⁺ release to myoplasmic Ca²⁺. Therefore, the increased fatigability of mutant EDL muscles can result from a combination of a slowing of Ca²⁺ uptake, modification of Ca²⁺-induced Ca²⁺ release (CICR), and a reduction in total SR Ca²⁺ content.

Keywords: MG29, mutant, skeletal muscle, skinned fibers, ECC, Ca²⁺ uptake, CICR.