Deficiency in Kelch protein Klhl31 causes congenital myopathy in mice

Papizan, James B.; Garry, Glynnis A.; Brezprozvannaya, Svetlana; McAnally, John; Bassel‐Duby, Rhonda; Liu, Ning; Olson, Eric N.

doi:10.1172/jci93445

Cited by 35 publications

(28 citation statements)

References 62 publications

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“…That reduction may have consequences as the Mef2c-regulated Klhl31 gene was also repressed ( Supplementary Tables 2 and 3). Klhl31 is associated with muscle differentiation 50 . The data of Wang et al on the induction of Zip14 by TNFα are supportive of earlier demonstrations of Zip14 induction by IL-6 and IL-1β in hepatocytes 11,51 and in adipose tissue 8 .…”

Section: Discussionmentioning

confidence: 99%

Deletion of metal transporter Zip14 (Slc39a14) produces skeletal muscle wasting, endotoxemia, Mef2c activation and induction of miR-675 and Hspb7

Kim

Aydemir

Jimenez

et al. 2020

Sci Rep

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Skeletal muscle represents the largest pool of body zinc, however, little is known about muscle zinc homeostasis or muscle-specific zinc functions. Zip14 (Slc39a14) was the most highly expressed zinc transporter in skeletal muscle of mice in response to LPS-induced inflammation. We compared metabolic parameters of skeletal muscle from global Zip14 knockout (KO) and wild-type mice (WT). At basal steady state Zip14 Ko mice exhibited a phenotype that included muscle wasting and metabolic endotoxemia. Microarray and qpcR analysis of gastrocnemius muscle RnA revealed that ablation of Zip14 produced increased muscle p-Mef2c, Hspb7 and miR-675-5p expression and increased p38 activation. chip assays showed enhanced binding of nf-κβ to the Mef2c promoter. in contrast, LpSinduced systemic inflammation enhanced Zip14-dependent zinc uptake by muscle, increased expression of Atrogin1 and MuRF1 and markedly reduced MyoD. these signatures of muscle atrophy and cachexia were not influenced by Zip14 ablation, however. LpS-induced miR-675-3p and-5p expression was Zip14-dependent. Collectively, these results with an integrative model are consistent with a Zip14 function in skeletal muscle at steady state that supports myogenesis through suppression of metabolic endotoxemia and that Zip14 ablation coincides with sustained activity of phosphorylated components of signaling pathways including p-Mef2c, which causes Hspb7-dependent muscle wasting.

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Section: Discussionmentioning

confidence: 99%

Deletion of metal transporter Zip14 (Slc39a14) produces skeletal muscle wasting, endotoxemia, Mef2c activation and induction of miR-675 and Hspb7

Kim

Aydemir

Jimenez

et al. 2020

Sci Rep

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“…KLHL9 is associated with a distal myopathy in humans 50 . KLHL31 is linked to a congenital myopathy in mice 51 . Furthermore, muscle-specific deletion of CUL3 disrupts muscle physiology profoundly, highlighting the fundamental importance of CUL3 and its substrate-specific adaptor molecules in muscle functions 40 .…”

Section: Discussionmentioning

confidence: 99%

Cullin3-RING ubiquitin ligases are intimately linked to the unfolded protein response of the endoplasmic reticulum

Moretti

Park

et al. 2018

Preprint

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CUL3-RING ubiquitin ligases (CRL3s) are involved in diverse cellular processes through over two hundred BTB-domain proteins. KLHL12, a BTB-domain protein, has been suggested to play an essential role in export of unusually large cargo molecules like procollagen from the endoplasmic reticulum (ER). It has been suggested that CRL3 KLHL12 mono-ubiquitinates SEC31 and mono-ubiquitinated SEC31 increases the dimension of a COPII coat to accommodate the large cargo molecules. As we examined this model, we found that functional CRL3 KLHL12 was indeed critical for the assembly of large COPII structures. However, it did not directly affect collagen secretion, but instead influenced collagen synthesis in human skin fibroblasts (HSFs).These results also suggest that there is a CRL3 KLHL12 -independent collagen secretion route. Unexpectedly, CRL3 KLHL12 strongly influenced the levels of sensors of the unfolded protein response (UPR) such as PERK and IRE1α. Interestingly, different cell lines reacted differently to CUL3 depletion. This cell-line dependency appears to rely on a cell-line specific BTB-domain protein(s) and a cell-line specific substrate(s) of the BTB-domain protein. Consistent with this idea, depletion of a muscle-specific BTB-domain protein KLHL41 recapitulated the effects of CUL3 depletion in C2C12 myotubes. Based on these results we propose that CRL3 KLHL12 and CRL3 KLHL41 are regulators of the UPR sensors. expression levels.

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“…Klhl31, a transcriptional repressor in MAPK/JNK signaling pathway, interacts with FLNC and promote Ub proteasome system-dependent degradation by ubiquitinating FLNC [62]. FLNC can also be ubiquitinated by the cardiac ubiquitin-proteasome system in Fbxl22-dependent fashion [67].…”

Section: Post-translational Modificationsmentioning

confidence: 99%

Structure and Function of Filamin C in the Muscle Z-Disc

Mao

Nakamura

2020

IJMS

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Filamin C (FLNC) is one of three filamin proteins (Filamin A (FLNA), Filamin B (FLNB), and FLNC) that cross-link actin filaments and interact with numerous binding partners. FLNC consists of a N-terminal actin-binding domain followed by 24 immunoglobulin-like repeats with two intervening calpain-sensitive hinges separating R15 and R16 (hinge 1) and R23 and R24 (hinge-2). The FLNC subunit is dimerized through R24 and calpain cleaves off the dimerization domain to regulate mobility of the FLNC subunit. FLNC is localized in the Z-disc due to the unique insertion of 82 amino acid residues in repeat 20 and necessary for normal Z-disc formation that connect sarcomeres. Since phosphorylation of FLNC by PKC diminishes the calpain sensitivity, assembly, and disassembly of the Z-disc may be regulated by phosphorylation of FLNC. Mutations of FLNC result in cardiomyopathy and muscle weakness. Although this review will focus on the current understanding of FLNC structure and functions in muscle, we will also discuss other filamins because they share high sequence similarity and are better characterized. We will also discuss a possible role of FLNC as a mechanosensor during muscle contraction.

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Deficiency in Kelch protein Klhl31 causes congenital myopathy in mice

Cited by 35 publications

References 62 publications

Deletion of metal transporter Zip14 (Slc39a14) produces skeletal muscle wasting, endotoxemia, Mef2c activation and induction of miR-675 and Hspb7

Deletion of metal transporter Zip14 (Slc39a14) produces skeletal muscle wasting, endotoxemia, Mef2c activation and induction of miR-675 and Hspb7

Cullin3-RING ubiquitin ligases are intimately linked to the unfolded protein response of the endoplasmic reticulum

Structure and Function of Filamin C in the Muscle Z-Disc

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