Contractile impairment and structural alterations of skeletal muscles from knockout mice lacking type 1 and type 3...

Skeletal muscle contraction is triggered by the release of Ca2+ from the sarcoplasmic reticulum through the type 1 ryanodine receptor (RyR1). Recently it has been shown that also the type 3 isoform of ryanodine receptor (RyR3), which is expressed in some mammalian skeletal muscles, may participate in the regulation of skeletal muscle contraction. Here we report the generation and the characterization of double mutant mice carrying a targeted disruption of both the RyR1 and the RyR3 genes (RyR1-/-;RyR3-/-). Skeletal muscles from mice homozygous for both mutations are unable to contract in response to caffeine and to ryanodine. In addition, they show a very poor capability to develop tension when directly activated with micromolar [Ca2+]i after membrane permeabilization which indicates either poor development or degeneration of the myofibrils. This was confirmed by biochemical analysis of contractile proteins. Electron microscopy confirms small size of myofibrils and shows complete absence of feet (RyRs) in the junctional SR.