title: Slowed relaxation and preserved maximal force in soleus muscles of mice with targeted disruption of the Serca2 gene in skeletal muscle.
abstract: Sarcoplasmic reticulum Ca(2+) ATPases (SERCAs) play a major role in muscle contractility by pumping Ca(2+) from the cytosol into the sarcoplasmic reticulum (SR) Ca(2+) store, allowing muscle relaxation and refilling of the SR with releasable Ca(2+). Decreased SERCA function has been shown to result in impaired muscle function and disease in human and animal models. In this study, we present a new mouse model with targeted disruption of the Serca2 gene in skeletal muscle (skKO) to investigate the functional consequences of reduced SERCA2 expression in skeletal muscle. SkKO mice were viable and basic muscle structure was intact. SERCA2 abundance was reduced in multiple muscles, and by as much as 95% in soleus muscle, having the highest content of slow-twitch fibres (40%). The Ca(2+) uptake rate was significantly reduced in SR vesicles in total homogenates. We did not find any compensatory increase in SERCA1 or SERCA3 abundance, or altered expression of several other Ca(2+)-handling proteins. Ultrastructural analysis revealed generally well-preserved muscle morphology, but a reduced volume of the longitudinal SR. In contracting soleus muscle in vitro preparations, skKO muscles were able to fully relax, but with a significantly slowed relaxation time compared to controls. Surprisingly, the maximal force and contraction rate were preserved, suggesting that skKO slow-twitch fibres may be able to contribute to the total muscle force despite loss of SERCA2 protein. Thus it is possible that SERCA-independent mechanisms can contribute to muscle contractile function.
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital, Ullevål, and University of Oslo, Oslo, Norway.
authors.forename: Cecilie
authors.initials: C
authors.lastname: Sjåland
authors.forename: Per Kristian
authors.initials: PK
authors.lastname: Lunde
authors.forename: Fredrik
authors.initials: F
authors.lastname: Swift
authors.forename: Morten
authors.initials: M
authors.lastname: Munkvik
authors.forename: Madelene
authors.initials: M
authors.lastname: Ericsson
authors.forename: Marianne
authors.initials: M
authors.lastname: Lunde
authors.forename: Sigurd
authors.initials: S
authors.lastname: Boye
authors.forename: Geir
authors.initials: G
authors.lastname: Christensen
authors.forename: Øyvind
authors.initials: Ø
authors.lastname: Ellingsen
authors.forename: Ole M
authors.initials: OM
authors.lastname: Sejersted
authors.forename: Kristin B
authors.initials: KB
authors.lastname: Andersson
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000502:physiology; D018657:Muscle Fibers, Slow-Twitch / Q000502:physiology; D009126:Muscle Relaxation / Q000502:physiology*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology*; D010805:Physical Conditioning, Animal / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506947:Atp2a2 protein, mouse; D002118:Calcium