The origin of tubular aggregates in human myopathies

Chevessier, Frédéric; Bauché, Stéphanie; Leroy, Jean‐Paul; Koenig, Jeanine; Paturneau-Jouas, Marion; Eymard, B.; Hantaı̈, Daniel; Verdière‐Sahuqué, Martine

doi:10.1002/path.1832

Cited by 79 publications

(119 citation statements)

References 40 publications

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“…4a and c, small arrows). Similar bridging structures have been also described in human TAs of patients suffering from TA myopathy (Chevessier et al 2005) and are only occasionally present in normal SR, where some flat cisternae are closely apposed (not shown). The nature of the SR-SR bridges is unknown, but SERCA can be excluded as a candidate, because the bridges appear as discrete elements, while the headpieces of SERCA form a continuous halo around the SR (Wang et al 1979;Campbell et al 1980).…”

Section: Resultsmentioning

confidence: 59%

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

Boncompagni

Protasi²,

Franzini‐Armstrong

2011

AGE

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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.

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Section: Resultsmentioning

confidence: 59%

“…The possible participation of mitochondria in TAs' formation is not confirmed (Engel 1964;Novotova et al 2002;Vielhaber et al 2001). Indeed mitochondrial markers are restricted to the periphery of TAs in human muscle (Chevessier et al 2005).…”

Section: Introductionmentioning

confidence: 99%

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

Boncompagni

Protasi²,

Franzini‐Armstrong

2011

AGE

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“…This hypothesis fits well, too, with the dearth of mitochondria, which can act as fast calcium sinks in skeletal muscle (31) as well as providing ATP for calcium uptake into the sarcoplasmic reticulum; their lack in Mstn Ϫ/Ϫ might well stimulate a compensatory formation of the sarcoplasmic reticulum. Intriguingly, small numbers of tubular aggregates are found in muscles of older male wild-type mice of the reference wild type used here and of various inbred and outbred laboratory mouse strains (32,33) but not in wild-type females, which correlates with the higher level of myostatin in wild-type female than male muscle (34).…”

Section: Discussionmentioning

confidence: 94%

Lack of myostatin results in excessive muscle growth but impaired force generation

Amthor

Macharia

Olivares-Navarrete

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

336

317

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The lack of myostatin promotes growth of skeletal muscle, and blockade of its activity has been proposed as a treatment for various muscle-wasting disorders. Here, we have examined two independent mouse lines that harbor mutations in the myostatin gene, constitutive null ( Mstn −/− ) and compact (Berlin High Line, BEH c/c ). We report that, despite a larger muscle mass relative to age-matched wild types, there was no increase in maximum tetanic force generation, but that when expressed as a function of muscle size (specific force), muscles of myostatin-deficient mice were weaker than wild-type muscles. In addition, Mstn −/− muscle contracted and relaxed faster during a single twitch and had a marked increase in the number of type IIb fibers relative to wild-type controls. This change was also accompanied by a significant increase in type IIB fibers containing tubular aggregates. Moreover, the ratio of mitochondrial DNA to nuclear DNA and mitochondria number were decreased in myostatin-deficient muscle, suggesting a mitochondrial depletion. Overall, our results suggest that lack of myostatin compromises force production in association with loss of oxidative characteristics of skeletal muscle.

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“…The latter is a rare muscle disease associated with muscle weakness and cramps in humans (Chevessier et al., 2005). In mouse models, the structure of TAs can be experimentally induced by anoxic conditions (Schiaffino, Severin, Cantini & Sartore, 1977).…”

Section: Discussionmentioning

confidence: 99%

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

Huang¹,

Shen²,

Wu³

et al. 2017

Aging Cell

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SummarySkeletal muscle has emerged as one of the most important tissues involved in regulating systemic metabolism. The gastrocnemius is a powerful skeletal muscle composed of predominantly glycolytic fast‐twitch fibers that are preferentially lost among old age. This decrease in gastrocnemius muscle mass is remarkable during aging; however, the underlying molecular mechanism is not fully understood. Strikingly, there is a ~70% decrease in Cisd2 protein, a key regulator of lifespan in mice and the disease gene for Wolfram syndrome 2 in humans, within the gastrocnemius after middle age among mice. A proteomics approach was used to investigate the gastrocnemius of naturally aged mice, and this was compared to the autonomous effect of Cisd2 on gastrocnemius aging using muscle‐specific Cisd2 knockout (mKO) mice as a premature aging model. Intriguingly, dysregulation of calcium signaling and activation of UPR/ER stress stand out as the top two pathways. Additionally, the activity of Serca1 was significantly impaired and this impairment is mainly attributable to irreversibly oxidative modifications of Serca. Our results reveal that the overall characteristics of the gastrocnemius are very similar when naturally aged mice and the Cisd2 mKO mice are compared in terms of pathological alterations, ultrastructural abnormalities, and proteomics profiling. This suggests that Cisd2 mKO mouse is a unique model for understanding the aging mechanism of skeletal muscle. Furthermore, this work substantiates the hypothesis that Cisd2 is crucial to the gastrocnemius muscle and suggests that Cisd2 is a potential therapeutic target for muscle aging.

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The origin of tubular aggregates in human myopathies

Cited by 79 publications

References 40 publications

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

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

Lack of myostatin results in excessive muscle growth but impaired force generation

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

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