Persistent upregulation of the β-tubulin tubb6, linked to muscle regeneration, is a source of microtubule disorganization in dystrophic muscle

Randazzo, Davide; Khalique, Umara; Belanto, Joseph J.; Kenea, Aster; Talsness, Dana M; Olthoff, John; Tran, Michelle D; Zaal, Kristien J.M.; Pak, Katherine; Pinal‐Fernandez, Iago; Mammen, Andrew L.; Sackett, Dan L.; Ervasti, James M.; Ralston, Evelyn

doi:10.1093/hmg/ddy418

Cited by 35 publications

(45 citation statements)

References 65 publications

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“…Tubb6 knockdown was found to be beneficial for microtubule organization in the DMD mouse model (Randazzo et al, 2019). Moreover, Tubb6 levels were higher in myofibers with central nuclei, suggesting a role in regeneration (Randazzo et al, 2019). Consistently, markers of regeneration are higher in shPab muscles (Olie et al, 2019), and we show that cytoskeleton disorganization in shPAB 2D cell culture is causally linked to reduced myogenesis.…”

Section: Discussionsupporting

confidence: 69%

“…Disrupted microtubule structures have been observed in muscular dystrophies such as Duchenne muscular dystrophy (DMD) (Khairallah, Shi et al, 2012). In a recent study, disrupted microtubule organization was found to be associated with higher levels of tubulin proteins (Randazzo, Khalique et al, 2019). We also found elevated levels of tubulin proteins in the shPab proteome, including β-tubulin6 (Tubb6) (Olie et al, 2019).…”

Section: Discussionmentioning

confidence: 63%

“…We also found elevated levels of tubulin proteins in the shPab proteome, including β-tubulin6 (Tubb6) (Olie et al, 2019). Tubb6 knockdown was found to be beneficial for microtubule organization in the DMD mouse model (Randazzo et al, 2019). Moreover, Tubb6 levels were higher in myofibers with central nuclei, suggesting a role in regeneration (Randazzo et al, 2019).…”

Section: Discussionmentioning

confidence: 79%

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Reduced PABPN1 levels causes cytoskeleton disorganization and aberrant differentiation

Domagoj

et al. 2020

Preprint

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The polyadenylation binding protein nucleus 1 (PABPN1), a multifactorial regulator of mRNA processing, regulates muscle wasting and atrophy. Previously, we elucidated the PABPN1-dependent proteome and found that levels of structural proteins, sarcomeric and cytoskeletal, were highly altered. We identified MURC, a plasma membrane-associated protein, to be affected by the cytoskeletal stability and suggest that MURC is a novel marker for impaired regeneration in muscles. We also studied the spatial organization of muscle structural proteins in 2D and 3D cell models with reduced PABPN1 levels (named here as shPAB). We show that dysregulation of cytoskeletal proteins in the shPab proteome is associated with a cytoskeleton lacking a polarized organization in muscle cells. We show that consequently, the cell mechanical features as well as myogenic differentiation are significantly reduced. We then show that restoring cytoskeletal stability, by actin overexpression in shPAB was beneficial for cell fusion and for the expression of sarcomeric proteins in shPAB models. We suggest that poor cytoskeleton mechanical features are caused by altered expression levels and contribute to agingassociated muscle wasting and atrophy.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 79%

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Reduced PABPN1 levels causes cytoskeleton disorganization and aberrant differentiation

Domagoj

et al. 2020

Preprint

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“…Disrupted microtubule structures have been observed in muscular dystrophies such as Duchenne muscular dystrophy (DMD) 43 . In a recent study, disrupted microtubule organization was found to be associated with higher levels of tubulin proteins 44 . We also found elevated levels of tubulin proteins in the shPab proteome, including β-tubulin6 (Tubb6) 5 .…”

Section: Discussionmentioning

confidence: 93%

Cytoskeletal disorganization underlies PABPN1-mediated myogenic disability

Olie

Wal

Domagoj

et al. 2020

Sci Rep

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Muscle wasting and atrophy are regulated by multiple molecular processes, including mRNA processing. Reduced levels of the polyadenylation binding protein nucleus 1 (PABPN1), a multifactorial regulator of mRNA processing, cause muscle atrophy. A proteomic study in muscles with reduced PABPN1 levels suggested dysregulation of sarcomeric and cytoskeletal proteins. Here we investigated the hypothesis that reduced PABPN1 levels lead to an aberrant organization of the cytoskeleton. MURC, a plasma membrane-associated protein, was found to be more abundant in muscles with reduced PABPN1 levels, and it was found to be expressed at regions showing regeneration. A polarized cytoskeletal organization is typical for muscle cells, but muscle cells with reduced PABPN1 levels (named as shPAB) were characterized by a disorganized cytoskeleton that lacked polarization. Moreover, cell mechanical features and myogenic differentiation were significantly reduced in shPAB cells. Importantly, restoring cytoskeletal stability, by actin overexpression, was beneficial for myogenesis, expression of sarcomeric proteins and proper localization of MURC in shPAB cell cultures and in shPAB muscle bundle. We suggest that poor cytoskeletal mechanical features are caused by altered expression levels of cytoskeletal proteins and contribute to muscle wasting and atrophy.

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“…It has been observed that, instead of well-organized microtubule lattice, DMD skeletal muscles showed largely disarranged microtubules. This was associated with the overexpression of the specific isoform of tubulin (beta 6 class V β-tubulin) pointing to the possible important role of this overexpression in DMD [153]. The study of mitochondrial bioenergetics demonstrated that, in permeabilized skeletal muscle fibers from mdx mice, the maximal rates of mitochondrial respiration were about twice lower than those of controls and similar changes were observed in skeletal muscle biopsies from DMD patients.…”

Section: Cytoskeletal-mitochondria Interactions In Pathologymentioning

confidence: 86%

Crosstalk between Mitochondria and Cytoskeleton in Cardiac Cells

Kuznetsov

Javadov

Grimm

et al. 2020

Cells

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Elucidation of the mitochondrial regulatory mechanisms for the understanding of muscle bioenergetics and the role of mitochondria is a fundamental problem in cellular physiology and pathophysiology. The cytoskeleton (microtubules, intermediate filaments, microfilaments) plays a central role in the maintenance of mitochondrial shape, location, and motility. In addition, numerous interactions between cytoskeletal proteins and mitochondria can actively participate in the regulation of mitochondrial respiration and oxidative phosphorylation. In cardiac and skeletal muscles, mitochondrial positions are tightly fixed, providing their regular arrangement and numerous interactions with other cellular structures such as sarcoplasmic reticulum and cytoskeleton. This can involve association of cytoskeletal proteins with voltage-dependent anion channel (VDAC), thereby, governing the permeability of the outer mitochondrial membrane (OMM) to metabolites, and regulating cell energy metabolism. Cardiomyocytes and myocardial fibers demonstrate regular arrangement of tubulin beta-II isoform entirely co-localized with mitochondria, in contrast to other isoforms of tubulin. This observation suggests the participation of tubulin beta-II in the regulation of OMM permeability through interaction with VDAC. The OMM permeability is also regulated by the specific isoform of cytolinker protein plectin. This review summarizes and discusses previous studies on the role of cytoskeletal proteins in the regulation of energy metabolism and mitochondrial function, adenosine triphosphate (ATP) production, and energy transfer.

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Persistent upregulation of the β-tubulin tubb6, linked to muscle regeneration, is a source of microtubule disorganization in dystrophic muscle

Cited by 35 publications

References 65 publications

Reduced PABPN1 levels causes cytoskeleton disorganization and aberrant differentiation

Reduced PABPN1 levels causes cytoskeleton disorganization and aberrant differentiation

Cytoskeletal disorganization underlies PABPN1-mediated myogenic disability

Crosstalk between Mitochondria and Cytoskeleton in Cardiac Cells

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