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

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

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Abstract

In healthy adult skeletal muscle fibers microtubules form a three-dimensional grid-like network. In the mdx mouse, a model of Duchenne muscular dystrophy (DMD),microtubules are mostly disordered, without periodicity. These microtubule defects have been linked to the mdx mouse pathology.We now report that increased expression of the beta 6 class V -tubulin (tubb6) contributes to the microtubule changes of mdx muscles.Wild-type muscle fibers overexpressing green f luorescent protein (GFP)-tubb6 (but not GFP-tubb5) have disorganized microtubules whereas mdx muscle fibers depleted of tubb6 (but not of tubb5) normalize their microtubules, suggesting that increasing tubb6 is toxic. However, tubb6 increases spontaneously during differentiation of mouse and human muscle cultures. Furthermore, endogenous tubb6 is not uniformly expressed in mdx muscles but is selectively increased in fiber clusters, which we identify as regenerating. Similarly, mdx-based rescued transgenic mice that retain a higher than expected tubb6 level show focal expression of tubb6 in subsets of fibers. Tubb6 is also upregulated in cardiotoxin-induced mouse muscle regeneration, in human myositis and DMD biopsies, and the tubb6 level correlates with that of embryonic myosin heavy chain, a regeneration marker. In conclusion,modulation of a -tubulin isotype plays a role in muscle differentiation and regeneration. Increased tubb6 expression and microtubule reorganization are not pathological per se but reflect a return to an earlier developmental stage. However, chronic elevation of tubb6, as occurs in the mdx mouse,may contribute to the repeated cycles of regeneration and to the pathology of the disease.

Original languageEnglish (US)
Pages (from-to)1117-1135
Number of pages19
JournalHuman molecular genetics
Volume28
Issue number7
DOIs
StatePublished - Jan 1 2019

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Tubulin
Microtubules
Regeneration
Up-Regulation
Muscles
Inbred mdx Mouse
Duchenne Muscular Dystrophy
Cardiotoxins
Pathology
Myositis
Myosin Heavy Chains
Poisons
Skeletal Muscle Fibers
Periodicity
Transgenic Mice
Proteins
Biopsy

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Randazzo, D., Khalique, U., Belanto, J. J., Kenea, A., Talsness, D. M., Olthoff, J. T., ... Ralston, E. (2019). Persistent upregulation of the β-tubulin tubb6, linked to muscle regeneration, is a source of microtubule disorganization in dystrophic muscle. Human molecular genetics, 28(7), 1117-1135. https://doi.org/10.1093/hmg/ddy418

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 T.; Tran, Michelle D.; Zaal, Kristien J.; Pak, Katherine; Pinal-Fernandez, Iago; Mammen, Andrew L.; Sackett, Dan; Ervasti, James M.; Ralston, Evelyn.

In: Human molecular genetics, Vol. 28, No. 7, 01.01.2019, p. 1117-1135.

Research output: Contribution to journalArticle

Randazzo, D, Khalique, U, Belanto, JJ, Kenea, A, Talsness, DM, Olthoff, JT, Tran, MD, Zaal, KJ, Pak, K, Pinal-Fernandez, I, Mammen, AL, Sackett, D, Ervasti, JM & Ralston, E 2019, 'Persistent upregulation of the β-tubulin tubb6, linked to muscle regeneration, is a source of microtubule disorganization in dystrophic muscle', Human molecular genetics, vol. 28, no. 7, pp. 1117-1135. https://doi.org/10.1093/hmg/ddy418
Randazzo, Davide ; Khalique, Umara ; Belanto, Joseph J. ; Kenea, Aster ; Talsness, Dana M. ; Olthoff, John T. ; Tran, Michelle D. ; Zaal, Kristien J. ; Pak, Katherine ; Pinal-Fernandez, Iago ; Mammen, Andrew L. ; Sackett, Dan ; Ervasti, James M. ; Ralston, Evelyn. / Persistent upregulation of the β-tubulin tubb6, linked to muscle regeneration, is a source of microtubule disorganization in dystrophic muscle. In: Human molecular genetics. 2019 ; Vol. 28, No. 7. pp. 1117-1135.
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abstract = "In healthy adult skeletal muscle fibers microtubules form a three-dimensional grid-like network. In the mdx mouse, a model of Duchenne muscular dystrophy (DMD),microtubules are mostly disordered, without periodicity. These microtubule defects have been linked to the mdx mouse pathology.We now report that increased expression of the beta 6 class V -tubulin (tubb6) contributes to the microtubule changes of mdx muscles.Wild-type muscle fibers overexpressing green f luorescent protein (GFP)-tubb6 (but not GFP-tubb5) have disorganized microtubules whereas mdx muscle fibers depleted of tubb6 (but not of tubb5) normalize their microtubules, suggesting that increasing tubb6 is toxic. However, tubb6 increases spontaneously during differentiation of mouse and human muscle cultures. Furthermore, endogenous tubb6 is not uniformly expressed in mdx muscles but is selectively increased in fiber clusters, which we identify as regenerating. Similarly, mdx-based rescued transgenic mice that retain a higher than expected tubb6 level show focal expression of tubb6 in subsets of fibers. Tubb6 is also upregulated in cardiotoxin-induced mouse muscle regeneration, in human myositis and DMD biopsies, and the tubb6 level correlates with that of embryonic myosin heavy chain, a regeneration marker. In conclusion,modulation of a -tubulin isotype plays a role in muscle differentiation and regeneration. Increased tubb6 expression and microtubule reorganization are not pathological per se but reflect a return to an earlier developmental stage. However, chronic elevation of tubb6, as occurs in the mdx mouse,may contribute to the repeated cycles of regeneration and to the pathology of the disease.",
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T1 - Persistent upregulation of the β-tubulin tubb6, linked to muscle regeneration, is a source of microtubule disorganization in dystrophic muscle

AU - Randazzo, Davide

AU - Khalique, Umara

AU - Belanto, Joseph J.

AU - Kenea, Aster

AU - Talsness, Dana M.

AU - Olthoff, John T.

AU - Tran, Michelle D.

AU - Zaal, Kristien J.

AU - Pak, Katherine

AU - Pinal-Fernandez, Iago

AU - Mammen, Andrew L.

AU - Sackett, Dan

AU - Ervasti, James M.

AU - Ralston, Evelyn

PY - 2019/1/1

Y1 - 2019/1/1

N2 - In healthy adult skeletal muscle fibers microtubules form a three-dimensional grid-like network. In the mdx mouse, a model of Duchenne muscular dystrophy (DMD),microtubules are mostly disordered, without periodicity. These microtubule defects have been linked to the mdx mouse pathology.We now report that increased expression of the beta 6 class V -tubulin (tubb6) contributes to the microtubule changes of mdx muscles.Wild-type muscle fibers overexpressing green f luorescent protein (GFP)-tubb6 (but not GFP-tubb5) have disorganized microtubules whereas mdx muscle fibers depleted of tubb6 (but not of tubb5) normalize their microtubules, suggesting that increasing tubb6 is toxic. However, tubb6 increases spontaneously during differentiation of mouse and human muscle cultures. Furthermore, endogenous tubb6 is not uniformly expressed in mdx muscles but is selectively increased in fiber clusters, which we identify as regenerating. Similarly, mdx-based rescued transgenic mice that retain a higher than expected tubb6 level show focal expression of tubb6 in subsets of fibers. Tubb6 is also upregulated in cardiotoxin-induced mouse muscle regeneration, in human myositis and DMD biopsies, and the tubb6 level correlates with that of embryonic myosin heavy chain, a regeneration marker. In conclusion,modulation of a -tubulin isotype plays a role in muscle differentiation and regeneration. Increased tubb6 expression and microtubule reorganization are not pathological per se but reflect a return to an earlier developmental stage. However, chronic elevation of tubb6, as occurs in the mdx mouse,may contribute to the repeated cycles of regeneration and to the pathology of the disease.

AB - In healthy adult skeletal muscle fibers microtubules form a three-dimensional grid-like network. In the mdx mouse, a model of Duchenne muscular dystrophy (DMD),microtubules are mostly disordered, without periodicity. These microtubule defects have been linked to the mdx mouse pathology.We now report that increased expression of the beta 6 class V -tubulin (tubb6) contributes to the microtubule changes of mdx muscles.Wild-type muscle fibers overexpressing green f luorescent protein (GFP)-tubb6 (but not GFP-tubb5) have disorganized microtubules whereas mdx muscle fibers depleted of tubb6 (but not of tubb5) normalize their microtubules, suggesting that increasing tubb6 is toxic. However, tubb6 increases spontaneously during differentiation of mouse and human muscle cultures. Furthermore, endogenous tubb6 is not uniformly expressed in mdx muscles but is selectively increased in fiber clusters, which we identify as regenerating. Similarly, mdx-based rescued transgenic mice that retain a higher than expected tubb6 level show focal expression of tubb6 in subsets of fibers. Tubb6 is also upregulated in cardiotoxin-induced mouse muscle regeneration, in human myositis and DMD biopsies, and the tubb6 level correlates with that of embryonic myosin heavy chain, a regeneration marker. In conclusion,modulation of a -tubulin isotype plays a role in muscle differentiation and regeneration. Increased tubb6 expression and microtubule reorganization are not pathological per se but reflect a return to an earlier developmental stage. However, chronic elevation of tubb6, as occurs in the mdx mouse,may contribute to the repeated cycles of regeneration and to the pathology of the disease.

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