Calcineurin Is Required for Skeletal Muscle Hypertrophy*
- From the Department of Chemistry and Biochemistry, Neuromuscular Research Laboratory, Laurentian University, Sudbury, Ontario P3E 2C6, Canada
Abstract
Molecular signaling pathways linking increases in skeletal muscle usage to alterations in muscle size have not been identified. In the present study, we tested the hypothesis that calcineurin, a calcium-regulated phosphatase recently implicated in the signaling of some forms of cardiomyopathic growth, is required to induce skeletal muscle hypertrophy and muscle fiber type conversions associated with functional overload in vivo. Administration of the specific calcineurin inhibitors cyclosporin (CsA) or FK506 to mice, for which the fast plantaris muscle was overloaded for 1–4 weeks, prevented the rapid doubling of mass and individual fiber size and the 4–20-fold increase in the number of slow fibers that characterize this condition. CsA treatment influenced the expression of muscle myofibrillar protein genes in a way reflective of fiber phenotype transformations but only in the long term of the overload condition, suggesting that the control of this growth response by calcineurin is not limited to the transcriptional activation of these muscle-specific genes. Clinically, these results provide insight to the post-surgical muscle wasting and weakness observed in recovering transplant recipients administered therapeutic dosages of these immunosuppressants.
Footnotes
-
↵* This work was supported in part by Natural Sciences and Engineering Research Council, Canada and the Ontario Thoracic Society (to R. N. M.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
-
↵‡ To whom correspondence should be addressed: Dept. of Chemistry & Biochemistry, Laurentian University, Ramsey Lake Rd., Sudbury, Ontario P3E 2C6, Canada. Tel.: 705-675-1151 (Ext. 1010); Fax: 705-675-4844; E-mail: rnmichel@nickel.laurentian.ca.
-
↵2 S. E. Dunn, J. L. Burns, and R. N. Michel, unpublished observations.
- Abbreviations:
- MHC
-
myosin heavy chain
- CsA
-
cyclosporin A
- OV
-
overloaded
- BrdUrd
-
5-bromo-2′-deoxyuridine
- RT-PCR
-
reverse transcription-polymerase chain reaction
- bp
-
base pair(s)
- TnIs
-
slow troponin I
- TnIf
-
fast troponin I
-
- Received February 16, 1999.
- Revision received May 19, 1999.
- The American Society for Biochemistry and Molecular Biology, Inc.
