Differential DNA methylation and transcriptional signatures characterize impairment of muscle stem cells in pediatric human muscle contractures after brain injury

Lydia A. Sibley; Nicole Broda; Wendy R. Gross; Austin F. Menezes; Ryan B. Embry; Vineeta T. Swaroop; Henry G. Chambers; Matthew J. Schipma; Richard L. Lieber; Andrea A. Domenighetti

doi:10.1096/fj.202100649R

Differential DNA methylation and transcriptional signatures characterize impairment of muscle stem cells in pediatric human muscle contractures after brain injury

Lydia A. Sibley, Nicole Broda, Wendy R. Gross, Austin F. Menezes, Ryan B. Embry, Vineeta T. Swaroop, Henry G. Chambers, Matthew J. Schipma, Richard L. Lieber, Andrea A. Domenighetti^*

^*Corresponding author for this work

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

12 Scopus citations

Abstract

Limb contractures are a debilitating and progressive consequence of a wide range of upper motor neuron injuries that affect skeletal muscle function. One type of perinatal brain injury causes cerebral palsy (CP), which affects a child's ability to move and is often painful. While several rehabilitation therapies are used to treat contractures, their long-term effectiveness is marginal since such therapies do not change muscle biological properties. Therefore, new therapies based on a biological understanding of contracture development are needed. Here, we show that myoblast progenitors from contractured muscle in children with CP are hyperproliferative. This phenotype is associated with DNA hypermethylation and specific gene expression patterns that favor cell proliferation over quiescence. Treatment of CP myoblasts with 5-azacytidine, a DNA hypomethylating agent, reduced this epigenetic imprint to TD levels, promoting exit from mitosis and molecular mechanisms of cellular quiescence. Together with previous studies demonstrating reduction in myoblast differentiation, this suggests a mechanism of contracture formation that is due to epigenetic modifications that alter the myogenic program of muscle-generating stem cells. We suggest that normalization of DNA methylation levels could rescue myogenesis and promote regulated muscle growth in muscle contracture and thus may represent a new nonsurgical approach to treating this devastating neuromuscular condition.

Original language	English (US)
Article number	e21928
Journal	FASEB Journal
Volume	35
Issue number	10
DOIs	https://doi.org/10.1096/fj.202100649R
State	Published - Oct 2021

Funding

The authors thank Ms Debbie Nutley for her support of this work. This work was supported by funds from Shirley Ryan AbilityLab, the Department of Physical Therapy & Human Movement Sciences at Northwestern University Feinberg School of Medicine, the Cures Within Reach and the Searle Funds at The Chicago Community Trust, and the Pedal‐with‐Pete Foundation with the American Academy of Cerebral Palsy and Developmental Medicine (AACPDM). This work was in part supported by a Research Career Scientist Award, Award Number IK6 RX003351 from the United States (U.S.) Department of Veterans Affairs Rehabilitation R&D (Rehab RD) Service. We acknowledge Dr Xinkun ‘Sequen’ Wang, Director of NUSeq Core Facility, Mr Alan Aalsburg from NuSeq Core Facility, Dr Marwan Baliki from Shirley Ryan AbilityLab, Dr Kenta Wakaizumi from Shirley Ryan AbilityLab for specific contributions to this study. The authors thank Ms Debbie Nutley for her support of this work. This work was supported by funds from Shirley Ryan AbilityLab, the Department of Physical Therapy & Human Movement Sciences at Northwestern University Feinberg School of Medicine, the Cures Within Reach and the Searle Funds at The Chicago Community Trust, and the Pedal-with-Pete Foundation with the American Academy of Cerebral Palsy and Developmental Medicine (AACPDM). This work was in part supported by a Research Career Scientist Award, Award Number IK6 RX003351 from the United States (U.S.) Department of Veterans Affairs Rehabilitation R&D (Rehab RD) Service. We acknowledge Dr Xinkun ‘Sequen’ Wang, Director of NUSeq Core Facility, Mr Alan Aalsburg from NuSeq Core Facility, Dr Marwan Baliki from Shirley Ryan AbilityLab, Dr Kenta Wakaizumi from Shirley Ryan AbilityLab for specific contributions to this study.

Keywords

5-azacytidine
DNA methylation
cerebral palsy
myoblast
satellite cell

ASJC Scopus subject areas

Genetics
Molecular Biology
Biochemistry
Biotechnology

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10.1096/fj.202100649R

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Sibley, L. A., Broda, N., Gross, W. R., Menezes, A. F., Embry, R. B., Swaroop, V. T., Chambers, H. G., Schipma, M. J., Lieber, R. L., & Domenighetti, A. A. (2021). Differential DNA methylation and transcriptional signatures characterize impairment of muscle stem cells in pediatric human muscle contractures after brain injury. FASEB Journal, 35(10), Article e21928. https://doi.org/10.1096/fj.202100649R

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title = "Differential DNA methylation and transcriptional signatures characterize impairment of muscle stem cells in pediatric human muscle contractures after brain injury",

abstract = "Limb contractures are a debilitating and progressive consequence of a wide range of upper motor neuron injuries that affect skeletal muscle function. One type of perinatal brain injury causes cerebral palsy (CP), which affects a child's ability to move and is often painful. While several rehabilitation therapies are used to treat contractures, their long-term effectiveness is marginal since such therapies do not change muscle biological properties. Therefore, new therapies based on a biological understanding of contracture development are needed. Here, we show that myoblast progenitors from contractured muscle in children with CP are hyperproliferative. This phenotype is associated with DNA hypermethylation and specific gene expression patterns that favor cell proliferation over quiescence. Treatment of CP myoblasts with 5-azacytidine, a DNA hypomethylating agent, reduced this epigenetic imprint to TD levels, promoting exit from mitosis and molecular mechanisms of cellular quiescence. Together with previous studies demonstrating reduction in myoblast differentiation, this suggests a mechanism of contracture formation that is due to epigenetic modifications that alter the myogenic program of muscle-generating stem cells. We suggest that normalization of DNA methylation levels could rescue myogenesis and promote regulated muscle growth in muscle contracture and thus may represent a new nonsurgical approach to treating this devastating neuromuscular condition.",

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author = "Sibley, {Lydia A.} and Nicole Broda and Gross, {Wendy R.} and Menezes, {Austin F.} and Embry, {Ryan B.} and Swaroop, {Vineeta T.} and Chambers, {Henry G.} and Schipma, {Matthew J.} and Lieber, {Richard L.} and Domenighetti, {Andrea A.}",

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Sibley, LA, Broda, N, Gross, WR, Menezes, AF, Embry, RB, Swaroop, VT, Chambers, HG, Schipma, MJ , Lieber, RL & Domenighetti, AA 2021, 'Differential DNA methylation and transcriptional signatures characterize impairment of muscle stem cells in pediatric human muscle contractures after brain injury', FASEB Journal, vol. 35, no. 10, e21928. https://doi.org/10.1096/fj.202100649R

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T1 - Differential DNA methylation and transcriptional signatures characterize impairment of muscle stem cells in pediatric human muscle contractures after brain injury

AU - Sibley, Lydia A.

AU - Broda, Nicole

AU - Gross, Wendy R.

AU - Menezes, Austin F.

AU - Embry, Ryan B.

AU - Swaroop, Vineeta T.

AU - Chambers, Henry G.

AU - Schipma, Matthew J.

AU - Lieber, Richard L.

AU - Domenighetti, Andrea A.

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N2 - Limb contractures are a debilitating and progressive consequence of a wide range of upper motor neuron injuries that affect skeletal muscle function. One type of perinatal brain injury causes cerebral palsy (CP), which affects a child's ability to move and is often painful. While several rehabilitation therapies are used to treat contractures, their long-term effectiveness is marginal since such therapies do not change muscle biological properties. Therefore, new therapies based on a biological understanding of contracture development are needed. Here, we show that myoblast progenitors from contractured muscle in children with CP are hyperproliferative. This phenotype is associated with DNA hypermethylation and specific gene expression patterns that favor cell proliferation over quiescence. Treatment of CP myoblasts with 5-azacytidine, a DNA hypomethylating agent, reduced this epigenetic imprint to TD levels, promoting exit from mitosis and molecular mechanisms of cellular quiescence. Together with previous studies demonstrating reduction in myoblast differentiation, this suggests a mechanism of contracture formation that is due to epigenetic modifications that alter the myogenic program of muscle-generating stem cells. We suggest that normalization of DNA methylation levels could rescue myogenesis and promote regulated muscle growth in muscle contracture and thus may represent a new nonsurgical approach to treating this devastating neuromuscular condition.

AB - Limb contractures are a debilitating and progressive consequence of a wide range of upper motor neuron injuries that affect skeletal muscle function. One type of perinatal brain injury causes cerebral palsy (CP), which affects a child's ability to move and is often painful. While several rehabilitation therapies are used to treat contractures, their long-term effectiveness is marginal since such therapies do not change muscle biological properties. Therefore, new therapies based on a biological understanding of contracture development are needed. Here, we show that myoblast progenitors from contractured muscle in children with CP are hyperproliferative. This phenotype is associated with DNA hypermethylation and specific gene expression patterns that favor cell proliferation over quiescence. Treatment of CP myoblasts with 5-azacytidine, a DNA hypomethylating agent, reduced this epigenetic imprint to TD levels, promoting exit from mitosis and molecular mechanisms of cellular quiescence. Together with previous studies demonstrating reduction in myoblast differentiation, this suggests a mechanism of contracture formation that is due to epigenetic modifications that alter the myogenic program of muscle-generating stem cells. We suggest that normalization of DNA methylation levels could rescue myogenesis and promote regulated muscle growth in muscle contracture and thus may represent a new nonsurgical approach to treating this devastating neuromuscular condition.

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Differential DNA methylation and transcriptional signatures characterize impairment of muscle stem cells in pediatric human muscle contractures after brain injury

Abstract

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Keywords

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