Multi-transcriptome analysis following an acute skeletal muscle growth stimulus yields tools for discerning global and MYC regulatory networks

Kevin A. Murach; Zhengye Liu; Baptiste Jude; Vandre C. Figueiredo; Yuan Wen; Sabin Khadgi; Seongkyun Lim; Francielly Morena da Silva; Nicholas P. Greene; Johanna T. Lanner; John J. McCarthy; Ivan J. Vechetti; Ferdinand von Walden

doi:10.1016/j.jbc.2022.102515

Multi-transcriptome analysis following an acute skeletal muscle growth stimulus yields tools for discerning global and MYC regulatory networks

Kevin A. Murach, Zhengye Liu, Baptiste Jude, Vandre C. Figueiredo, Yuan Wen, Sabin Khadgi, Seongkyun Lim, Francielly Morena da Silva, Nicholas P. Greene, Johanna T. Lanner, John J. McCarthy, Ivan J. Vechetti, Ferdinand von Walden

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

Myc is a powerful transcription factor implicated in epigenetic reprogramming, cellular plasticity, and rapid growth as well as tumorigenesis. Cancer in skeletal muscle is extremely rare despite marked and sustained Myc induction during loading-induced hypertrophy. Here, we investigated global, actively transcribed, stable, and myonucleus-specific transcriptomes following an acute hypertrophic stimulus in mouse plantaris. With these datasets, we define global and Myc-specific dynamics at the onset of mechanical overload-induced muscle fiber growth. Data collation across analyses reveals an under-appreciated role for the muscle fiber in extracellular matrix remodeling during adaptation, along with the contribution of mRNA stability to epigenetic-related transcript levels in muscle. We also identify Runx1 and Ankrd1 (Marp1) as abundant myonucleus-enriched loading-induced genes. We observed that a strong induction of cell cycle regulators including Myc occurs with mechanical overload in myonuclei. Additionally, in vivo Myc-controlled gene expression in the plantaris was defined using a genetic muscle fiber-specific doxycycline-inducible Myc-overexpression model. We determined Myc is implicated in numerous aspects of gene expression during early-phase muscle fiber growth. Specifically, brief induction of Myc protein in muscle represses Reverbα, Reverbβ, and Myh2 while increasing Rpl3, recapitulating gene expression in myonuclei during acute overload. Experimental, comparative, and in silico analyses place Myc at the center of a stable and actively transcribed, loading-responsive, muscle fiber–localized regulatory hub. Collectively, our experiments are a roadmap for understanding global and Myc-mediated transcriptional networks that regulate rapid remodeling in postmitotic cells. We provide open webtools for exploring the five RNA-seq datasets as a resource to the field.

Original language	English
Article number	102515
Journal	Journal of Biological Chemistry
Volume	298
Issue number	11
DOIs	https://doi.org/10.1016/j.jbc.2022.102515
State	Published - Nov 2022

Bibliographical note

Funding Information:
This work was supported by NIH R00 AG063994 and startup funds from the University of Arkansas Vice Chancellor for Research and Innovation to K. A. M., support from NIH P20GM104320-07 to I. J. V., and support from AFM-Telethon 23137 , SMDF , Åke Wiberg , Swedish Medical Association , and the Swedish Research Council for Sport Science to F. v. W., Z. L. was supported by the Chinese Scholarship Council . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding Information:
The TRE-Myc mouse was a generous gift from Dr Andrew McMahon at the University of Southern California. The authors thank Dr Christopher Sundberg of Marquette University for his thoughtful comments on our work, Dr Charlotte Peterson and the University Kentucky Center for Muscle Biology for resources and support, Dr C. Brooks Mobley for assistance with mouse colony management, and Dr Qian (Alvin) Qin of Harvard University for input on Lisa. Figures 1A and 5 were created using BioRender. K. A. M. I. J. V. and F. v. W. conceptualization; K. A. M. N. P. G. J. T. L. J. J. M. I. J. V. and F. v. W. funding acquisition; K. A. M. B. J. V. C. F. Y. W. S. K. S. L. F. M. d. S. I. J. V. and F. v. W. investigation; K. A. M. Z. L. B. J. V. C. F. Y. W. S. K. S. L. F. M. d. S. I. J. V. and F. v. W. formal analysis; K. A. M. N. P. G. J. T. L. J. J. M. I. J. V. and F. v. W. supervision; K. A. M. Z. L. B. J. V. C. F. Y. W. S. K. S. L. F. M. d. S. N. P. G. J. T. L. J. J. M. I. J. V. and F. v. W. writing–review and editing; Z. L. data curation; K. A. M. and Z. L. methodology; K. A. M. writing–original draft. This work was supported by NIH R00 AG063994 and startup funds from the University of Arkansas Vice Chancellor for Research and Innovation to K. A. M. support from NIH P20GM104320-07 to I. J. V. and support from AFM-Telethon 23137, SMDF, Åke Wiberg, Swedish Medical Association, and the Swedish Research Council for Sport Science to F. v. W. Z. L. was supported by the Chinese Scholarship Council. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2022 The Authors

Keywords

5-Ethenyl uridine
Ankrd1
Rpl3
Runx1
Warburg effect
gene transcription
muscle hypertrophy
myonuclei
myosin
transcriptomics

ASJC Scopus subject areas

Biochemistry
Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jbc.2022.102515

Cite this

Murach, K. A., Liu, Z., Jude, B., Figueiredo, V. C., Wen, Y., Khadgi, S., Lim, S., Morena da Silva, F., Greene, N. P., Lanner, J. T., McCarthy, J. J., Vechetti, I. J., & von Walden, F. (2022). Multi-transcriptome analysis following an acute skeletal muscle growth stimulus yields tools for discerning global and MYC regulatory networks. Journal of Biological Chemistry, 298(11), Article 102515. https://doi.org/10.1016/j.jbc.2022.102515

@article{60fd537b70de44ba8c48de460d0347ce,

title = "Multi-transcriptome analysis following an acute skeletal muscle growth stimulus yields tools for discerning global and MYC regulatory networks",

abstract = "Myc is a powerful transcription factor implicated in epigenetic reprogramming, cellular plasticity, and rapid growth as well as tumorigenesis. Cancer in skeletal muscle is extremely rare despite marked and sustained Myc induction during loading-induced hypertrophy. Here, we investigated global, actively transcribed, stable, and myonucleus-specific transcriptomes following an acute hypertrophic stimulus in mouse plantaris. With these datasets, we define global and Myc-specific dynamics at the onset of mechanical overload-induced muscle fiber growth. Data collation across analyses reveals an under-appreciated role for the muscle fiber in extracellular matrix remodeling during adaptation, along with the contribution of mRNA stability to epigenetic-related transcript levels in muscle. We also identify Runx1 and Ankrd1 (Marp1) as abundant myonucleus-enriched loading-induced genes. We observed that a strong induction of cell cycle regulators including Myc occurs with mechanical overload in myonuclei. Additionally, in vivo Myc-controlled gene expression in the plantaris was defined using a genetic muscle fiber-specific doxycycline-inducible Myc-overexpression model. We determined Myc is implicated in numerous aspects of gene expression during early-phase muscle fiber growth. Specifically, brief induction of Myc protein in muscle represses Reverbα, Reverbβ, and Myh2 while increasing Rpl3, recapitulating gene expression in myonuclei during acute overload. Experimental, comparative, and in silico analyses place Myc at the center of a stable and actively transcribed, loading-responsive, muscle fiber–localized regulatory hub. Collectively, our experiments are a roadmap for understanding global and Myc-mediated transcriptional networks that regulate rapid remodeling in postmitotic cells. We provide open webtools for exploring the five RNA-seq datasets as a resource to the field.",

keywords = "5-Ethenyl uridine, Ankrd1, Rpl3, Runx1, Warburg effect, gene transcription, muscle hypertrophy, myonuclei, myosin, transcriptomics",

author = "Murach, {Kevin A.} and Zhengye Liu and Baptiste Jude and Figueiredo, {Vandre C.} and Yuan Wen and Sabin Khadgi and Seongkyun Lim and {Morena da Silva}, Francielly and Greene, {Nicholas P.} and Lanner, {Johanna T.} and McCarthy, {John J.} and Vechetti, {Ivan J.} and {von Walden}, Ferdinand",

note = "Funding Information: This work was supported by NIH R00 AG063994 and startup funds from the University of Arkansas Vice Chancellor for Research and Innovation to K. A. M., support from NIH P20GM104320-07 to I. J. V., and support from AFM-Telethon 23137 , SMDF , {\AA}ke Wiberg , Swedish Medical Association , and the Swedish Research Council for Sport Science to F. v. W., Z. L. was supported by the Chinese Scholarship Council . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: The TRE-Myc mouse was a generous gift from Dr Andrew McMahon at the University of Southern California. The authors thank Dr Christopher Sundberg of Marquette University for his thoughtful comments on our work, Dr Charlotte Peterson and the University Kentucky Center for Muscle Biology for resources and support, Dr C. Brooks Mobley for assistance with mouse colony management, and Dr Qian (Alvin) Qin of Harvard University for input on Lisa. Figures 1A and 5 were created using BioRender. K. A. M. I. J. V. and F. v. W. conceptualization; K. A. M. N. P. G. J. T. L. J. J. M. I. J. V. and F. v. W. funding acquisition; K. A. M. B. J. V. C. F. Y. W. S. K. S. L. F. M. d. S. I. J. V. and F. v. W. investigation; K. A. M. Z. L. B. J. V. C. F. Y. W. S. K. S. L. F. M. d. S. I. J. V. and F. v. W. formal analysis; K. A. M. N. P. G. J. T. L. J. J. M. I. J. V. and F. v. W. supervision; K. A. M. Z. L. B. J. V. C. F. Y. W. S. K. S. L. F. M. d. S. N. P. G. J. T. L. J. J. M. I. J. V. and F. v. W. writing–review and editing; Z. L. data curation; K. A. M. and Z. L. methodology; K. A. M. writing–original draft. This work was supported by NIH R00 AG063994 and startup funds from the University of Arkansas Vice Chancellor for Research and Innovation to K. A. M. support from NIH P20GM104320-07 to I. J. V. and support from AFM-Telethon 23137, SMDF, {\AA}ke Wiberg, Swedish Medical Association, and the Swedish Research Council for Sport Science to F. v. W. Z. L. was supported by the Chinese Scholarship Council. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = nov,

doi = "10.1016/j.jbc.2022.102515",

language = "English",

volume = "298",

number = "11",

}

Murach, KA, Liu, Z, Jude, B, Figueiredo, VC, Wen, Y, Khadgi, S, Lim, S, Morena da Silva, F, Greene, NP, Lanner, JT, McCarthy, JJ, Vechetti, IJ & von Walden, F 2022, 'Multi-transcriptome analysis following an acute skeletal muscle growth stimulus yields tools for discerning global and MYC regulatory networks', Journal of Biological Chemistry, vol. 298, no. 11, 102515. https://doi.org/10.1016/j.jbc.2022.102515

TY - JOUR

T1 - Multi-transcriptome analysis following an acute skeletal muscle growth stimulus yields tools for discerning global and MYC regulatory networks

AU - Murach, Kevin A.

AU - Liu, Zhengye

AU - Jude, Baptiste

AU - Figueiredo, Vandre C.

AU - Wen, Yuan

AU - Khadgi, Sabin

AU - Lim, Seongkyun

AU - Morena da Silva, Francielly

AU - Greene, Nicholas P.

AU - Lanner, Johanna T.

AU - McCarthy, John J.

AU - Vechetti, Ivan J.

AU - von Walden, Ferdinand

N1 - Funding Information: This work was supported by NIH R00 AG063994 and startup funds from the University of Arkansas Vice Chancellor for Research and Innovation to K. A. M., support from NIH P20GM104320-07 to I. J. V., and support from AFM-Telethon 23137 , SMDF , Åke Wiberg , Swedish Medical Association , and the Swedish Research Council for Sport Science to F. v. W., Z. L. was supported by the Chinese Scholarship Council . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Funding Information: The TRE-Myc mouse was a generous gift from Dr Andrew McMahon at the University of Southern California. The authors thank Dr Christopher Sundberg of Marquette University for his thoughtful comments on our work, Dr Charlotte Peterson and the University Kentucky Center for Muscle Biology for resources and support, Dr C. Brooks Mobley for assistance with mouse colony management, and Dr Qian (Alvin) Qin of Harvard University for input on Lisa. Figures 1A and 5 were created using BioRender. K. A. M. I. J. V. and F. v. W. conceptualization; K. A. M. N. P. G. J. T. L. J. J. M. I. J. V. and F. v. W. funding acquisition; K. A. M. B. J. V. C. F. Y. W. S. K. S. L. F. M. d. S. I. J. V. and F. v. W. investigation; K. A. M. Z. L. B. J. V. C. F. Y. W. S. K. S. L. F. M. d. S. I. J. V. and F. v. W. formal analysis; K. A. M. N. P. G. J. T. L. J. J. M. I. J. V. and F. v. W. supervision; K. A. M. Z. L. B. J. V. C. F. Y. W. S. K. S. L. F. M. d. S. N. P. G. J. T. L. J. J. M. I. J. V. and F. v. W. writing–review and editing; Z. L. data curation; K. A. M. and Z. L. methodology; K. A. M. writing–original draft. This work was supported by NIH R00 AG063994 and startup funds from the University of Arkansas Vice Chancellor for Research and Innovation to K. A. M. support from NIH P20GM104320-07 to I. J. V. and support from AFM-Telethon 23137, SMDF, Åke Wiberg, Swedish Medical Association, and the Swedish Research Council for Sport Science to F. v. W. Z. L. was supported by the Chinese Scholarship Council. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: © 2022 The Authors

PY - 2022/11

Y1 - 2022/11

N2 - Myc is a powerful transcription factor implicated in epigenetic reprogramming, cellular plasticity, and rapid growth as well as tumorigenesis. Cancer in skeletal muscle is extremely rare despite marked and sustained Myc induction during loading-induced hypertrophy. Here, we investigated global, actively transcribed, stable, and myonucleus-specific transcriptomes following an acute hypertrophic stimulus in mouse plantaris. With these datasets, we define global and Myc-specific dynamics at the onset of mechanical overload-induced muscle fiber growth. Data collation across analyses reveals an under-appreciated role for the muscle fiber in extracellular matrix remodeling during adaptation, along with the contribution of mRNA stability to epigenetic-related transcript levels in muscle. We also identify Runx1 and Ankrd1 (Marp1) as abundant myonucleus-enriched loading-induced genes. We observed that a strong induction of cell cycle regulators including Myc occurs with mechanical overload in myonuclei. Additionally, in vivo Myc-controlled gene expression in the plantaris was defined using a genetic muscle fiber-specific doxycycline-inducible Myc-overexpression model. We determined Myc is implicated in numerous aspects of gene expression during early-phase muscle fiber growth. Specifically, brief induction of Myc protein in muscle represses Reverbα, Reverbβ, and Myh2 while increasing Rpl3, recapitulating gene expression in myonuclei during acute overload. Experimental, comparative, and in silico analyses place Myc at the center of a stable and actively transcribed, loading-responsive, muscle fiber–localized regulatory hub. Collectively, our experiments are a roadmap for understanding global and Myc-mediated transcriptional networks that regulate rapid remodeling in postmitotic cells. We provide open webtools for exploring the five RNA-seq datasets as a resource to the field.

AB - Myc is a powerful transcription factor implicated in epigenetic reprogramming, cellular plasticity, and rapid growth as well as tumorigenesis. Cancer in skeletal muscle is extremely rare despite marked and sustained Myc induction during loading-induced hypertrophy. Here, we investigated global, actively transcribed, stable, and myonucleus-specific transcriptomes following an acute hypertrophic stimulus in mouse plantaris. With these datasets, we define global and Myc-specific dynamics at the onset of mechanical overload-induced muscle fiber growth. Data collation across analyses reveals an under-appreciated role for the muscle fiber in extracellular matrix remodeling during adaptation, along with the contribution of mRNA stability to epigenetic-related transcript levels in muscle. We also identify Runx1 and Ankrd1 (Marp1) as abundant myonucleus-enriched loading-induced genes. We observed that a strong induction of cell cycle regulators including Myc occurs with mechanical overload in myonuclei. Additionally, in vivo Myc-controlled gene expression in the plantaris was defined using a genetic muscle fiber-specific doxycycline-inducible Myc-overexpression model. We determined Myc is implicated in numerous aspects of gene expression during early-phase muscle fiber growth. Specifically, brief induction of Myc protein in muscle represses Reverbα, Reverbβ, and Myh2 while increasing Rpl3, recapitulating gene expression in myonuclei during acute overload. Experimental, comparative, and in silico analyses place Myc at the center of a stable and actively transcribed, loading-responsive, muscle fiber–localized regulatory hub. Collectively, our experiments are a roadmap for understanding global and Myc-mediated transcriptional networks that regulate rapid remodeling in postmitotic cells. We provide open webtools for exploring the five RNA-seq datasets as a resource to the field.

KW - 5-Ethenyl uridine

KW - Ankrd1

KW - Rpl3

KW - Runx1

KW - Warburg effect

KW - gene transcription

KW - muscle hypertrophy

KW - myonuclei

KW - myosin

KW - transcriptomics

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UR - http://www.scopus.com/inward/citedby.url?scp=85140138820&partnerID=8YFLogxK

U2 - 10.1016/j.jbc.2022.102515

DO - 10.1016/j.jbc.2022.102515

M3 - Article

C2 - 36150502

AN - SCOPUS:85140138820

SN - 0021-9258

VL - 298

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 11

M1 - 102515

ER -

Multi-transcriptome analysis following an acute skeletal muscle growth stimulus yields tools for discerning global and MYC regulatory networks

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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