Abstract
Tubular aggregates (TAs), ordered arrays of elongated sarcoplasmic reticulum (SR) tubules, are present in skeletal muscle from patients with myopathies and are also experimentally induced by extreme anoxia. In wild-type mice TAs develop in a clear age-, sex- (male), and fiber type- (fast twitch) dependence. However, the events preceding the appearance of TAs have not been explored. We investigated the sequential stages leading to the initial appearance and maturation of TAs in EDL from male mice. TAs’ formation requires two temporally distinct steps that operate via different mechanisms. Initially (before 1 year of age), the SR Ca2+ binding protein calsequestrin (CASQ) accumulates specifically at the I band level causing swelling of free SR cisternae. In the second stage, the enlarged SR sacs at the I band level extend into multiple, longitudinally oriented tubules with a full complement of sarco(endo)plasmic reticulum Ca2+ ATPases (SERCA) in the membrane and CASQ in the lumen. Tubules gradually acquire a regular cylindrical shape and uniform size apparently in concert with partial crystallization of SERCA. Multiple, small TAs associate to form fewer mature TAs of very large size. Interestingly, in fibers from CASQ1-knockout mice abnormal aggregates of SR tubules have different conformation and never develop into ordered aggregates of straight cylinders, possibly due to lack of CASQ accumulation. We conclude that TAs do not arise abruptly but are the final result of a gradually changing SR architecture and we suggest that the crystalline ATPase within the aggregates may be inactive.
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Abbreviations
- TAs:
-
Tubular aggregates
- CRUs:
-
Calcium release units
- EM:
-
Electron microscopy
- CASQ:
-
Calsequestrin
- SR:
-
Sarcoplasmic reticulum
- jSR:
-
Junctional SR
- TT:
-
T-tubule transverse tubule
- SERCAs:
-
Sarco(endo)plasmic reticulum Ca2+ ATPases
- DHPR:
-
Dihydropyridine receptor
- RYRs:
-
Ryanodine receptors
- WT:
-
Wild type
- CM:
-
Confocal microscopy
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Acknowledgements
We thank Drs. Osvaldo Delbono and Cecilia Paolini for providing samples of aged female mice and CASQ1 null mice used in this study. We thank L. R. Jones (Indiana University) for the generous gift of anti CASQ antibody 4B1.D3. This study was supported by National Institutes of Health Grant 5P01AR052354 to C.F.A. and by Telethon Research Grant GGP08153 to F.P.
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Boncompagni, S., Protasi, F. & Franzini-Armstrong, C. Sequential stages in the age-dependent gradual formation and accumulation of tubular aggregates in fast twitch muscle fibers: SERCA and calsequestrin involvement. AGE 34, 27–41 (2012). https://doi.org/10.1007/s11357-011-9211-y
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DOI: https://doi.org/10.1007/s11357-011-9211-y