A mutation in desmin makes skeletal muscle less vulnerable to acute muscle damage after eccentric loading in rats

Langer, Henning T.; Mossakowski, Agata A.; Avey, Alec; Wohlgemuth, Ross P.; Smith, Lucas; Zbinden-Foncea, Herman; Baar, Keith

doi:10.1096/fj.202100711rr

Cited by 9 publications

(7 citation statements)

References 61 publications

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“…( C ) Western blot of LC3A/B in muscle extracts from CTL, ECC, MORB (and an age-matched control AGED), SAL, and INS. The ratio of LC3II/LC3I is elevated under increased autophagic flux, which is expected with eccentric exercise and critical illness, but not with insulin treatment ( Banduseela et al, 2013 ; Langer et al, 2021 ). Raw data and statistical analysis results for relative MuRF1 and MAFbx gene expression, ubiquitin/Ponceau, and LC3II/LC3I.…”

Section: Resultsmentioning

confidence: 89%

Tenotomy-induced muscle atrophy is sex-specific and independent of NFκB

Meyer¹,

Thomopoulos

Abu‐Amer

et al. 2022

eLife

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The nuclear factor-κB (NFκB) pathway is a major thoroughfare for skeletal muscle atrophy and is driven by diverse stimuli. Targeted inhibition of NFκB through its canonical mediator IKKβ effectively mitigates loss of muscle mass across many conditions, from denervation to unloading to cancer. In this study, we used gain- and loss-of-function mouse models to examine the role of NFκB in muscle atrophy following rotator cuff tenotomy - a model of chronic rotator cuff tear. IKKβ was knocked down or constitutively activated in muscle-specific inducible transgenic mice to elicit a 2-fold gain or loss of NFκB signaling. Surprisingly, neither knockdown of IKKβ nor overexpression of caIKKβ significantly altered the loss of muscle mass following tenotomy. This finding was consistent across measures of morphological adaptation (fiber cross-sectional area, fiber length, fiber number), tissue pathology (fibrosis and fatty infiltration) and intracellular signaling (ubiquitin-proteasome, autophagy). Intriguingly, late-stage tenotomy-induced atrophy was exacerbated in male mice compared to female mice. This sex specificity was driven by ongoing decreases in fiber cross-sectional area, which paralleled the accumulation of large autophagic vesicles in male, but not female muscle. These findings suggest that tenotomy-induced atrophy is not dependent on NFκB and instead may be regulated by autophagy in a sex-specific manner.

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Section: Resultsmentioning

confidence: 89%

Tenotomy-induced muscle atrophy is sex-specific and independent of NFκB

Meyer¹,

Thomopoulos

Abu‐Amer

et al. 2022

eLife

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show abstract

“…We used the injection of puromycin, a tRNA analog known to be incorporated into any de novo peptide that is being synthesized after administration ( 64 , 65 ). Through a puromycin antibody, in vivo global protein synthesis can then be assessed via immunoblot analysis as described previously ( 32 , 66 ). We blotted puromycin levels in liver tissue from our experiment since the macroscopic changes in the liver seemed to closely mirror whole body changes in mass ( Fig.…”

Section: Resultsmentioning

confidence: 99%

The proteasome regulates body weight and systemic nutrient metabolism during fasting

Langer,

Taylor,

Ahmed

et al. 2023

American Journal of Physiology-Endocrinology and Metabolism

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Background: The ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway are the primary means of degradation in mammalian tissues. We sought to determine the individual contribution of the UPS and autophagy to tissue catabolism during fasting.Methods: Mice were overnight fasted for 15h before regaining food access ("Fed" group, n=6) or continuing to fast ("Fast" group, n=7) for 3h. Additionally, to investigate the effects of autophagy on systemic metabolism and tissue degradation, one group of mice was fasted for 18h and treated with chloroquine ("Fast+CLQ" group, n=7), and a fourth group of mice was treated with bortezomib ("Fast+Bort" group, n=7) to assess the contribution of the UPS. Body weight, tissue weight, circulating hormones and metabolites, intracellular signaling pathways, and protein synthesis were investigated.Results: Fasting induced the loss of body weight, liver mass, and white adipose tissue in the Fast and the Fast+CLQ group, while the Fast+Bort group maintained tissue and body weight. Fasting reduced glucose and increased beta hydroxybutyrate in the circulation of all mice. Both changes were most profound in the Fast+Bort group compared to the other fasting conditions. Molecular signaling indicated a successful inhibition of hepatic UPS with bortezomib and an upregulation of the PI3K/AKT/mTOR pathway. The latter was further supported by an increase in hepatic protein synthesis with bortezomib.Conclusion: Inhibition of the UPS through bortezomib blocks body weight loss and tissue catabolism during an acute overnight fast in mice. The effects were likely mediated through a combined effect of the drug on biomolecule degradation and synthesis.

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“…Finally, CSRP3 or muscle-specific LIM (mLIM) has been reported to have essential roles in myogenesis and differentiation [ 40 ], as well as to interact with cytoskeletal proteins such as actin [ 41 ] and sense mechanical stress at the z-disc [ 42 ]. We have recently found mLIM to be robustly increased in another model of muscular dystrophy (‘desminopathy’) and in response to muscle-damaging exercise [ 43 ]. In the study at hand, levels of mLIM did not differ significantly between the DDp53 and the contralateral control leg ( p = 0.75) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Dominant-negative p53-overexpression in skeletal muscle induces cell death and fiber atrophy in rats

et al. 2022

Self Cite

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The tumor suppressor p53 is thought to play a key role in the maintenance of cell size and homeostasis, but relatively little is known about its role in skeletal muscle. Based on its ability to suppress cell growth, we hypothesized that inhibiting the function of wild-type p53 through the overexpression of a dominant-negative p53 mutant (DDp53) could result in muscle fiber hypertrophy. To test this hypothesis, we electroporated adult rat tibialis anterior muscles with DDp53 and collected the tissue three weeks later. We confirmed successful overexpression of DDp53 on a histological and biochemical level and found pronounced changes to muscle architecture, metabolism, and molecular signaling. Muscle mass, fiber cross-sectional area, and fiber diameter significantly decreased with DDp53 overexpression. We found histopathological changes in DDp53 transfected muscle which were accompanied by increased levels of proteins that are associated with membrane damage and repair. In addition, DDp53 decreased oxidative phosphorylation complex I and V protein levels, and despite its negative effects on muscle mass and fiber size, caused an increase in muscle protein synthesis as assessed via the SUnSET technique. Interestingly, the increase in muscle protein synthesis was concomitant with a decrease in phospho-S6K1 (Thr389). Furthermore, the muscle wasting in the DDp53 electroporated leg was accompanied by a decrease in global protein ubiquitination and an increase in proteasome activity. In conclusion, overexpression of a dominant-negative p53 mutant in skeletal muscle results in decreased muscle mass, myofiber size, histological muscle damage, a metabolic phenotype, and perturbed homeostasis between muscle protein synthesis and degradation.

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A mutation in desmin makes skeletal muscle less vulnerable to acute muscle damage after eccentric loading in rats

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 9 publications

References 61 publications

Tenotomy-induced muscle atrophy is sex-specific and independent of NFκB

Tenotomy-induced muscle atrophy is sex-specific and independent of NFκB

The proteasome regulates body weight and systemic nutrient metabolism during fasting

Dominant-negative p53-overexpression in skeletal muscle induces cell death and fiber atrophy in rats

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