The E3 ubiquitin ligase Asb2β is downregulated in a mouse model of hypertrophic cardiomyopathy and targets desmin for proteasomal degradation

Thottakara, Tilo; Friedrich, Felix W.; Reischmann, Silke; Braumann, Simon; Schlossarek, Saskia; Krämer, Elisabeth; Juhr, Denise; Schlüter, Hartmut; Velden, Jolanda van der; Münch, Julia; Patten, Monica; Eschenhagen, Thomas; Moog-Lutz, Christel; Carrier, Lucie

doi:10.1016/j.yjmcc.2015.08.020

Cited by 33 publications

(37 citation statements)

References 62 publications

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“…In addition, ASB2 , has considerable expression in heart although it meets our criteria for a SkM gene. ASB2 is abnormally down-regulated in a mouse model for hypertrophic cardiomyopathy with an associated buildup of desmin levels due to loss of ASB2-directed proteosomal-mediated degradation in cardiomyocytes [70]. Similarly, ASB2 can be a negative regulator of SkM mass [71].…”

Section: Discussionmentioning

confidence: 99%

Epigenetics of skeletal muscle-associated genes in theASB, LRRC, TMEM, andOSBPLgene families

Ehrlich¹,

Lacey

Ehrlich

2019

Preprint

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Much remains to be discovered about the intersection of tissue-specific transcription control and the epigenetics of skeletal muscle (SkM), a very complex and dynamic organ. From four gene families, ASB, LRRC, TMEM, and OSBPL, we chose 21 genes that are preferentially expressed in human SkM relative to 52 other tissue types and analyzed relationships between their tissue-specific epigenetics and expression. We also compared their genetics, proteomics, and descriptions in the literature. For this study, we identified genes with little or no previous descriptions of SkM functionality (ASB4, ASB8, ASB10, ASB12, ASB16, LRRC14B, LRRC20, LRRC30, TMEM52, TMEM233, OSBPL6/ORP6, and OSBPL11/ORP11) and included genes whose SkM functions had been previously addressed (ASB2, ASB5, ASB11, ASB15, LRRC2, LRRC38, LRRC39, TMEM38A/TRIC-A, and TMEM38B/TRIC-B). Among the transcription-related SkM epigenetic features that we identified were super-enhancers, promoter DNA hypomethylation, lengthening of constitutive low-methylated promoter regions, and SkM-related enhancers for one gene embedded in a neighboring gene (e.g., ASB8-PFKM, LRRC39-DBT, and LRRC14B-PLEKHG4B gene-pairs). In addition, highly or lowly co-expressed long non-coding RNA (lncRNA) genes probably regulate several of these genes. Our findings give insights into tissue-specific epigenetic patterns and functionality of related genes in a gene family and can elucidate normal and disease-related regulation of gene expression in SkM.

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Section: Discussionmentioning

confidence: 99%

Epigenetics of skeletal muscle-associated genes in theASB, LRRC, TMEM, andOSBPLgene families

Ehrlich¹,

Lacey

Ehrlich

2019

Preprint

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“…This suggests that ASB2’s target proteins are important mediators of muscle hypertrophy through a mechanism independent of the protein synthesis pathway. Currently, characterized targets of ASB2 include members of the filamin family (filaminA/B), which are critical in the organization and stability of f-actin fibers (35, 36, 43) and desmin (44). This supports our observation that protein synthesis activation through the mTOR pathway is insufficient to solely account for FST-stimulated muscle hypertrophy (32), and this model incorporates components beyond protein synthesis regulation, of which Asb2 is a critical member.…”

Section: Discussionmentioning

confidence: 99%

Integrated expression analysis of muscle hypertrophy identifies Asb2 as a negative regulator of muscle mass

et al. 2016

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The transforming growth factor-β (TGF-β) signaling network is a critical regulator of skeletal muscle mass and function and, thus, is an attractive therapeutic target for combating muscle disease, but the underlying mechanisms of action remain undetermined. We report that follistatin-based interventions (which modulate TGF-β network activity) can promote muscle hypertrophy that ameliorates aging-associated muscle wasting. However, the muscles of old sarcopenic mice demonstrate reduced response to follistatin compared with healthy young-adult musculature. Quantitative proteomic and transcriptomic analyses of young-adult muscles identified a transcription/translation signature elicited by follistatin exposure, which included repression of ankyrin repeat and SOCS box protein 2 (Asb2). Increasing expression of ASB2 reduced muscle mass, thereby demonstrating that Asb2 is a TGF-β network–responsive negative regulator of muscle mass. In contrast to young-adult muscles, sarcopenic muscles do not exhibit reduced ASB2 abundance with follistatin exposure. Moreover, preventing repression of ASB2 in young-adult muscles diminished follistatin-induced muscle hypertrophy. These findings provide insight into the program of transcription and translation events governing follistatin-mediated adaptation of skeletal muscle attributes and identify Asb2 as a regulator of muscle mass implicated in the potential mechanistic dysfunction between follistatin-mediated muscle growth in young and old muscles.

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“…27 All materials from patients and donors were taken with informed consent of the donors and with approval of the local ethical boards and according to the Declaration of Helsinki.…”

Section: Methodsmentioning

confidence: 99%

Activation of Autophagy Ameliorates Cardiomyopathy in Mybpc3 -Targeted Knockin Mice

Singh

Zech

Geertz

et al. 2017

Circ: Heart Failure

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Background Alterations in autophagy have been reported in hypertrophic cardiomyopathy (HCM) caused by Danon disease, Vici syndrome or LEOPARD syndrome, but not in HCM caused by mutations in genes encoding sarcomeric proteins, which account for most of HCM cases. MYBPC3, encoding cardiac myosin-binding protein C, is the most frequently mutated HCM gene. Methods and Results We evaluated autophagy in HCM patients carrying MYBPC3 mutations and in a Mybpc3-targeted knock-in (KI) HCM mouse model, as well as the effect of autophagy modulators on the development of cardiomyopathy in KI mice. Microtubule-associated protein 1 light chain 3 (LC3)-II protein levels were higher in HCM septal myectomies than in non-failing control hearts and in 60-week-old KI than wild-type (WT) mouse hearts. In contrast to WT, autophagic flux was blunted and associated with accumulation of residual bodies and glycogen in hearts of 60-week-old KI mice. We found that Akt-mTORC1 signaling was increased, and treatment with 2.24 mg/kgxd rapamycin or 40% caloric restriction for 9 weeks partially rescued cardiomyopathy or heart failure and restored autophagic flux in KI mice. Conclusions Altogether, we found that i) autophagy is altered in HCM patients with MYBPC3 mutations, ii) autophagy is impaired in Mybpc3-targeted KI mice and iii) activation of autophagy ameliorated the cardiac disease phenotype in this mouse model. We propose that activation of autophagy might be an attractive option alone or in combination with another therapy to rescue HCM caused by MYBPC3 mutations.

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The E3 ubiquitin ligase Asb2β is downregulated in a mouse model of hypertrophic cardiomyopathy and targets desmin for proteasomal degradation

Cited by 33 publications

References 62 publications

Epigenetics of skeletal muscle-associated genes in theASB, LRRC, TMEM, andOSBPLgene families

Epigenetics of skeletal muscle-associated genes in theASB, LRRC, TMEM, andOSBPLgene families

Integrated expression analysis of muscle hypertrophy identifies Asb2 as a negative regulator of muscle mass

Activation of Autophagy Ameliorates Cardiomyopathy in Mybpc3 -Targeted Knockin Mice

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