Sequential stages in the age-dependent gradual formation and accumulation of tubular aggregates in fast twitch muscle fibers: SERCA and calsequestrin involvement

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 Ca 2+ 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 Ca 2+ 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.

Comparative proteomic profiling reveals a role for Cisd2 in skeletal muscle aging

“…Furthermore, a previous study has shown that Casq and Serca both participate in TA development. As TAs appear to be associated with myopathy, Serca located in the TA membrane has been suggested to be inactivated or functionally compromised (Boncompagni, Protasi & Franzini‐Armstrong, 2012). Consistent with the above, our current findings in mice, and previous findings using a rat model (Sharov, Dremina, Galeva, Williams & Schoneich, 2006), have both revealed that Serca activity decreases in an age‐dependent manner and this decrease in Serca activity is correlated inversely with increased oxidative modification, namely cysteine sulfonation and 3‐nitrotyrosine, which occurs as a consequence of oxidative stress and aging.…”

Background data on NOD/Shi-<i>scid</i> IL-2Rγ^null mice (NOG mice)

“…Electron microscopic examination revealed that these inclusions consisted of dilated and accumulated sarcoplasmic reticula arranging in an orderly manner. In wild-type mice, they are known as tubular aggregates in muscle cells and reported to be detected only in male mice (Agbulut et al, 2000;Boncompagni et al, 2012). Therefore, it was interesting that in NOG mice, the change occurred not only in males but also in females.…”

Clinical, histological and genetic characterisation of patients with tubular aggregate myopathy caused by mutations in STIM1

“…Tubular aggregates originate from the SR,18 23 24 and it has been proposed that sequential formation of aggregates in ageing skeletal muscle fibres is initiated by swelling of the SR cisternae and their extension into longitudinally oriented tubules 22. Different proteins involved in the uptake and the storage of Ca 2+ such as STIM1, SERCA1, RYR1, sarcalumenin or triadin were previously shown to be components of the aggregates 16 18.…”

“…Tubular aggregates are the only histopathological hallmark in tubular aggregate myopathy and were most often detected in type II muscle fibres. They also appear in muscle disorders as hypokalemic periodic paralysis19 or congenital limb-girdle myasthenia,20 21 and strikingly accumulate in normal muscle with age in mammals 22…”