Excitation-contraction uncoupling and muscular degeneration in mice lacking functional skeletal muscle ryanodine-receptor gene

• Published in: Nature (London) Vol. 369; no. 6481; pp. 556 - 559
• Main Authors: Takeshima, Hiroshi, lino, Masamitsu, Takekura, Hiroaki, Nishi, Miyuki, Kuno, Junko, Minowa, Osamu, Takano, Hiroshi, Noda, Tetsuo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 16.06.1994; Nature Publishing Group
• Subjects: Animals; Base Sequence; Biological and medical sciences; Calcium Channels - deficiency; Calcium Channels - genetics; Calcium Channels - physiology; Cell Line; Chimera; Cloning; Deoxyribonucleic acid; DNA; Electric Stimulation; Fetal Death - genetics; Fundamental and applied biological sciences. Psychology; Genetics; Male; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Muscle Contraction - physiology; Muscle Proteins - deficiency; Muscle Proteins - genetics; Muscle Proteins - physiology; Muscles - physiology; Muscles - physiopathology; Muscles - ultrastructure; Mutation; Proteins - analysis; RNA - analysis; Rodents; Ryanodine Receptor Calcium Release Channel; Striated muscle. Tendons; Vertebrates: osteoarticular system, musculoskeletal system; Ryanodine; Alkaloid; Vertebrata; Mammalia; Calcium; Excitation contraction coupling; Mouse; Rodentia; Ionic channel; Striated muscle; Muscle contraction; Biological receptor
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/369556a0

Contraction of skeletal muscle is triggered by the release of Ca2+ from the sarcoplasmic reticulum (SR) after depolarization of transverse tubules. The ryanodine receptor exists as a 'foot' protein in the junctional gap between the sarcoplasmic reticulum and the transverse tubule in skeletal muscle, and is proposed to function as a calcium-release channel during excitation-contraction (E-C) coupling. Previous complementary DNA-cloning studies have defined three distinct subtypes of the ryanodine receptor in mammalian tissues, namely skeletal muscle, cardiac and brain types. We report here mice with a targeted mutation in the skeletal muscle ryanodine receptor gene. Mice homozygous for the mutation die perinatally with gross abnormalities of the skeletal muscle. The contractile response to electrical stimulation under physiological conditions is totally abolished in the mutant muscle, although ryanodine receptors other than the skeletal-muscle type seem to exist because the response to caffeine is retained. Our results show that the skeletal muscle ryanodine receptor is essential for both muscular maturation and E-C coupling, and also imply that the function of the skeletal muscle ryanodine receptor during E-C coupling cannot be substituted by other subtypes of the receptor.