| Autor: |
Thekkedam CG; Eccles Institute of Neuroscience, John Curtin School of Medical Research, Australian National University, Acton, ACT 2601, Australia., Dutka TL; Department of Animal, Plant and Soil Sciences, School of Agriculture, Biomedicine and Environment (SABE), La Trobe University, Melbourne, VIC 3086, Australia., Van der Poel C; Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Melbourne, VIC 3086, Australia., Burgio G; Division of Genome Sciences and Cancer, John Curtin School of Medical Research, Australian National University, Acton, ACT 2601, Australia., Dulhunty AF; Eccles Institute of Neuroscience, John Curtin School of Medical Research, Australian National University, Acton, ACT 2601, Australia. |
| Abstrakt: |
The recessive Ryanodine Receptor Type 1 (RyR1) P3527S mutation causes mild muscle weakness in patients and increased resting cytoplasmic [Ca 2+ ] in transformed lymphoblastoid cells. In the present study, we explored the cellular/molecular effects of this mutation in a mouse model of the mutation (RyR1 P3528S). The results were obtained from 73 wild type (WT/WT), 82 heterozygous (WT/MUT) and 66 homozygous (MUT/MUT) mice with different numbers of observations in individual data sets depending on the experimental protocol. The results showed that WT/MUT and MUT/MUT mouse strength was less than that of WT/WT mice, but there was no difference between genotypes in appearance, weight, mobility or longevity. The force frequency response of extensor digitorum longus (EDL) and soleus (SOL) muscles from WT/MUT and MUT/MUT mice was shifter to higher frequencies. The specific force of EDL muscles was reduced and Ca 2+ activation of skinned fibres shifted to a lower [Ca 2+ ], with an increase in type I fibres in EDL muscles and in mixed type I/II fibres in SOL muscles. The relative activity of RyR1 channels exposed to 1 µM cytoplasmic Ca 2+ was greater in WT/MUT and MUT/MUT mice than in WT/WT mice. We suggest the altered RyR1 activity due to the P2328S substitution could increase resting [Ca 2+ ] in muscle fibres, leading to changes in fibre type and contractile properties. |
