Modulation of Sarcoplasmic Reticulum Calcium Pump (SERCA) Function by Membrane Cholesterol during Unloading

Mathematics – Logic

Scientific paper

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Scientific paper

We have recently demonstrated by in situ immuno-localization that cholesterol is predominantly located in the sarcoplasmic reticulum (SR), rather than in the sarcolemmal/T-tubule (SL-TT) membranes of both human and rat skeletal muscle (Clarke et al., 2000, JAP). In addition, we have demonstrated that mechanical unloading of skeletal muscle in a rat hindlimb suspension model significantly increases membrane cholesterol content and that this increase is also localized to SR rather than SL-TT membranes in such atrophied muscle. Utilizing a novel fluorescent calcium staining technique in perfusion fixed soleus muscle we observed a significant positive correlation between membrane cholesterol content and free intramyofiber calcium levels during unloading. To determine if a correlation between increased SR membrane cholesterol content and increased free intramyofiber calcium levels during unloading is due to a membrane cholesterol-mediated alteration in SR calcium pump function, we also describe the effects of modulating the cholesterol content of purified SR membrane preparations on SR-Ca2+ ATPase activity and ryanodine channel activity. As an increase in free intra-cellular calcium levels have previously demonstrated to induce catabolism in a wide range of biological systems, we suggest that altered SR calcium pump function may be the underlying basis for the initiation of unloading induced muscle atrophy.

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