Age-related appearance of tubular aggregates in the skeletal muscle of almost all male inbred mice

Abstract

Tubular aggregates (TAs) which have been recently observed in a few mouse myopathies are identical to those described in human diseases. In this study we show that TAs are also found in the skeletal muscle of almost all normal inbred mice strains. In these inbred strains of mice the presence of TAs is shown to be related to both age and sex. Nine different muscles were stained with the modified Gomori trichrome method to reveal the general morphology of the muscles. Anti-SERCA1 ATPase was used to confirm that the TAs were in fact accumulations of sarcoplasmic reticulum and anti-MyHC IIB to demonstrate that these accumulations were found exclusively in the type IIB muscle fibers. An ultrastructural study confirmed the observations revealed by light microscopy that the TAs were derived from the sarcoplasmic reticulum. TAs were never observed in female inbred mice and were only found in type IIB glycolytic muscle fibers of male inbred mice. Therefore when analyzing the effect of genetic knock out and knock in experiments on the muscle phenotype of transgenic mice one should be aware that the presence of these aggregates is a non-specific phenomenon induced by inbreeding.

PGC-1α regulates mitochondrial calcium homeostasis, SR stress and cell death to mitigate skeletal muscle aging

“…Overload of SR function results in a compensatory increase in SR membranes and ultimately the development of tubular aggregates, e.g. as reported in muscle fibers of old mice (38). On histological sections, we noticed the presence of abnormal eosinlabeled structures in tibialis anterior (TA) muscles of old WT and mKO-PGC-1α animals ( Fig.…”

“…Tubular aggregates are predominantly composed of small, densely packed tubules arising from sarcoplasmic reticulum (39) and are associated with both natural and premature aging in mice (38,51). In humans, tubular aggregates have likewise been reported in old muscle (52), but are also prominently observed in several other pathological conditions, including peripheral neuropathies, amyotrophic lateral sclerosis and myotonic dystrophy (53)(54)(55).…”

Effects of loaded voluntary wheel exercise on performance and muscle hypertrophy in young and old male C57Bl/6J mice

“…In ageing muscle (20-21 months), branched/split myofibers are also evident and a recent study in isolated myofibers demonstrates that they occur without evidence of regeneration, indicating a different and unknown mechanism for this phenomenon (Pichavant & Pavlath, 2014). Another pathology that is widely reported only in ageing male mouse muscles is the accumulation of tubular aggregates: while these increase in male muscles from 6 months of age they were not seen in any muscles of female mice examined up to 19 (Agbulut et al, 2000;Nishikawa et al, 2000;Chevessier et al, 2004) or even at 24 months of age (Kuncl et al, 1989). Thus, issues of gender need to be carefully considered when discussing such pathological changes in old rodent muscles.…”

Identification and characterization of three novel mutations in theCASQ1gene in four patients with tubular aggregate myopathy

“…The processes leading to the formation of these structures are not fully understood. Tubular aggregates formation has been proposed to result from aggregation of SR-derived membranes possibly caused by misfolding and aggregation of SR proteins as a consequence of hereditary or acquired conditions (Agbulut, Destombes, Thiesson, & Butler-Browne, 2000;Chevessier et al, 2005;Giacomello et al, 2015;Kuncl, Pestronk, Lane, & Alexander, 1989;Schiaffino, 2012). Activating mutations in STIM1 have been also detected in patients with Stormorken syndrome, who present thrombocytopenia and bleeding diathesis in association with miosis and TAM (Misceo et al, 2014;Nesin et al, 2014).…”