Slowed relaxation and preserved maximal force in soleus muscles of mice with targeted disruption of theSerca2gene in skeletal muscle

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Abstract

Non–technical summary

Muscle function depends on tightly regulated Ca2+ movement between the intracellular sarcoplasmic reticulum (SR) Ca2+ store and cytoplasm in muscle cells. Disturbances in these processes have been linked to impaired muscle function and muscle disease. We disrupted the gene for the SERCA2 SR Ca2+ pump in mouse skeletal muscle to study how decreased transport of Ca2+ into the SR would affect soleus muscle function. We found that the SERCA2 content was strongly reduced in the 40% fraction of soleus muscle fibres normally expressing SERCA2. Muscle relaxation was slowed, supporting the hypothesis that reduced SERCA2 would reduce Ca2+ transport into the SR and prolong muscle relaxation time. Surprisingly, the muscles maintained maximal force, despite the fact that less SERCA2 in these fibres would be expected to lower the amount of Ca2+ released during contraction, and thereby lower the maximal force. Our findings raise important questions regarding the roles of SERCA2 and SR in muscle function.

Sarcoplasmic reticulum Ca2+ ATPases (SERCAs) play a major role in muscle contractility by pumping Ca2+ from the cytosol into the sarcoplasmic reticulum (SR) Ca2+ store, allowing muscle relaxation and refilling of the SR with releasable Ca2+. 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 Ca2+ 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 Ca2+–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.

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