Perturbations in intracellular Ca 2+ handling in skeletal muscle in the G93ASOD1 mouse model of amyotrophic lateral sclerosis

• Published in: American Journal of Physiology: Cell Physiology 2014-12, Vol.307 (11), p.C1031-C1038
• Main Authors: Chin, Eva R., Chen, Dapeng, Bobyk, Kostyantyn D., Mázala, Davi A. G.
• Format: Article
• Language: English
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.00237.2013

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by skeletal muscle atrophy and weakness, ultimately leading to respiratory failure. The purpose of this study was to assess changes in skeletal muscle excitation-contraction (E-C) coupling and intracellular Ca 2+ handling during disease progression in the G93A*SOD1 ALS transgenic (ALS Tg) mouse model. To assess E-C coupling, single muscle fibers were electrically stimulated (10–150 Hz), and intracellular free Ca 2+ concentration was assessed using fura-2. There were no differences in peak fura-2 ratio at any stimulation frequency at 70 days (early presymptomatic). However, at 90 days (late presymptomatic) and 120–140 days (symptomatic), fura-2 ratio was increased at 10 Hz in ALS Tg compared with wild-type (WT) fibers (0.670 ± 0.02 vs. 0.585 ± 0.02 for 120–140 days; P < 0.05). There was also a significant increase in resting fura-2 ratio at 90 days (0.351 ± 0.008 vs. 0.390 ± 0.009 in WT vs. ALS Tg; P < 0.05) and 120–140 days (0.374 ± 0.001 vs. 0.415 ± 0.003 in WT vs. ALS Tg; P < 0.05). These increases in intracellular Ca 2+ in ALS Tg muscle were associated with reductions in the sarcoplasmic/endoplasmic reticulum Ca 2+ ATPase proteins SERCA1 (to 54% and 19% of WT) and SERCA2 (to 56% and 11% of WT) and parvalbumin (to 80 and 62% of WT) in gastrocnemius muscle at 90 and 120–140 days, respectively. There was no change in dihydropyridine receptor/l-type Ca 2+ channel at any age. Overall, these data demonstrate minimal changes in electrically evoked Ca 2+ transients but elevations in intracellular Ca 2+ attributable to decreased Ca 2+ -clearance proteins. These data suggest that elevations in cellular Ca 2+ could contribute to muscle weakness during disease progression in ALS mice.