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Am J Physiol Endocrinol Metab (July 24, 2002). doi:10.1152/ajpendo.00242.2002
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Articles in PresS, published online ahead of print July 23, 2002
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00242.2002
Submitted on June 4, 2002
Accepted on July 17, 2002

Intermittent increases in cytosolic Ca2+ stimulate mitochondrial bioenesis in muscle cells

Edward O Ojuka1, Terry E Jones1, Dong-Ho Han1, May Chen1, Brian R Wamhoff2, Michael Sturek2, and John O Holloszy1*

1 Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
2 Departments of Physiology and Internal Medicine, University of Missouri, Columbia, Missouri, USA

* To whom correspondence should be addressed. E-mail: jhollosz{at}im.wustl.edu.

Muscle contractions cause numerous disturbances in intracellular homeostasis. This makes it impossible to use contracting muscle to identify which of the many signals generated by contractions are responsible for stimulating mitochondrial biogenesis. One purpose of this study was to evaluate the usefulness of L6 myotubes, which do not contract, for studying mitochondrial biogenesis. A second purpose was to further evaluate the possibility that increases in cytosolic Ca2+ can stimulate mitochondrial biogenesis. Continuous exposure to 1 µM ionomycin, a Ca2+ ionophore, for 5d induced an increase in mitochondrial enzymes, but also caused a loss of myotubes, as reflected in a ~40% decrease in protein per dish. However, intermittent (5h/d) exposure to ionomycin, or to caffeine or W7, which release Ca2+ from the sarcoplasmic reticulum, did not cause a decrease in protein per dish. Raising cytosolic Ca2+ intermittently with these agents induced significant increases in mitochondrial enzymes. EGTA blocked most of this effect of ionomycin, while dantrolene, which blocks Ca2+ release from the SR, largely prevented the increases in mitochondrial enzymes induced by W7 and caffeine. These findings provide evidence that intermittently raising cytosolic Ca2+ stimulates mitochondrial biogenesis in muscle cells.




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