p21 induces a senescence program and skeletal muscle dysfunction

Davis A. Englund; Alyssa Jolliffe; Zaira Aversa; Xu Zhang; Ines Sturmlechner; Ayumi E. Sakamoto; Julianna D. Zeidler; Gina M. Warner; Colton McNinch; Thomas A. White; Eduardo N. Chini; Darren J. Baker; Jan M. van Deursen; Nathan K. LeBrasseur

doi:10.1016/j.molmet.2022.101652

p21 induces a senescence program and skeletal muscle dysfunction

Davis A. Englund, Alyssa Jolliffe, Zaira Aversa, Xu Zhang, Ines Sturmlechner, Ayumi E. Sakamoto, Julianna D. Zeidler, Gina M. Warner, Colton McNinch, Thomas A. White, Eduardo N. Chini, Darren J. Baker, Jan M. van Deursen, Nathan K. LeBrasseur^*

^*Corresponding author for this work

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

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Abstract

Recent work has established associations between elevated p21, the accumulation of senescent cells, and skeletal muscle dysfunction in mice and humans. Using a mouse model of p21 overexpression (p21OE), we examined if p21 mechanistically contributes to cellular senescence and pathological features in skeletal muscle. We show that p21 induces several core properties of cellular senescence in skeletal muscle, including an altered transcriptome, DNA damage, mitochondrial dysfunction, and the senescence-associated secretory phenotype (SASP). Furthermore, p21OE mice exhibit manifestations of skeletal muscle pathology, such as atrophy, fibrosis, and impaired physical function when compared to age-matched controls. These findings suggest p21 alone is sufficient to drive a cellular senescence program and reveal a novel source of skeletal muscle loss and dysfunction.

Original language	English
Article number	101652
Number of pages	11
Journal	Molecular metabolism
Volume	67
Early online date	9-Dec-2022
DOIs	https://doi.org/10.1016/j.molmet.2022.101652
Publication status	Published - Jan-2023

Keywords

Aging
Cellular senescence
DNA damage
Fibrosis
Physical function
Sarcopenia
Senescence-associated secretory phenotype

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p21 induces a senescence program and skeletal muscle dysfunctionFinal publisher's version, 3.51 MBLicence: Taverne

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Englund, D. A., Jolliffe, A., Aversa, Z., Zhang, X., Sturmlechner, I., Sakamoto, A. E., Zeidler, J. D., Warner, G. M., McNinch, C., White, T. A., Chini, E. N., Baker, D. J., van Deursen, J. M., & LeBrasseur, N. K. (2023). p21 induces a senescence program and skeletal muscle dysfunction. Molecular metabolism, 67, Article 101652. https://doi.org/10.1016/j.molmet.2022.101652

@article{6ac26817f65b4ad0b59dce98fb6a1a24,

title = "p21 induces a senescence program and skeletal muscle dysfunction",

abstract = "Recent work has established associations between elevated p21, the accumulation of senescent cells, and skeletal muscle dysfunction in mice and humans. Using a mouse model of p21 overexpression (p21OE), we examined if p21 mechanistically contributes to cellular senescence and pathological features in skeletal muscle. We show that p21 induces several core properties of cellular senescence in skeletal muscle, including an altered transcriptome, DNA damage, mitochondrial dysfunction, and the senescence-associated secretory phenotype (SASP). Furthermore, p21OE mice exhibit manifestations of skeletal muscle pathology, such as atrophy, fibrosis, and impaired physical function when compared to age-matched controls. These findings suggest p21 alone is sufficient to drive a cellular senescence program and reveal a novel source of skeletal muscle loss and dysfunction.",

keywords = "Aging, Cellular senescence, DNA damage, Fibrosis, Physical function, Sarcopenia, Senescence-associated secretory phenotype",

author = "Englund, {Davis A.} and Alyssa Jolliffe and Zaira Aversa and Xu Zhang and Ines Sturmlechner and Sakamoto, {Ayumi E.} and Zeidler, {Julianna D.} and Warner, {Gina M.} and Colton McNinch and White, {Thomas A.} and Chini, {Eduardo N.} and Baker, {Darren J.} and {van Deursen}, {Jan M.} and LeBrasseur, {Nathan K.}",

note = "Funding Information: This work was supported by NIH NATIONAL INSTITUTE ON AGING grants to N.K.L ( AG060907, AG062413, and AG055529 ) and D.A.E and I.S (T32AG049672), the Glenn Foundation for Medical Research (N.K.L, E.N.C, and D.J.B) and the Pritzker Foundation (N.K.L). Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2023",

month = jan,

doi = "10.1016/j.molmet.2022.101652",

language = "English",

volume = "67",

journal = "Molecular metabolism",

issn = "2212-8778",

publisher = "ELSEVIER SCIENCE BV",

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TY - JOUR

T1 - p21 induces a senescence program and skeletal muscle dysfunction

AU - Englund, Davis A.

AU - Jolliffe, Alyssa

AU - Aversa, Zaira

AU - Zhang, Xu

AU - Sturmlechner, Ines

AU - Sakamoto, Ayumi E.

AU - Zeidler, Julianna D.

AU - Warner, Gina M.

AU - McNinch, Colton

AU - White, Thomas A.

AU - Chini, Eduardo N.

AU - Baker, Darren J.

AU - van Deursen, Jan M.

AU - LeBrasseur, Nathan K.

N1 - Funding Information: This work was supported by NIH NATIONAL INSTITUTE ON AGING grants to N.K.L ( AG060907, AG062413, and AG055529 ) and D.A.E and I.S (T32AG049672), the Glenn Foundation for Medical Research (N.K.L, E.N.C, and D.J.B) and the Pritzker Foundation (N.K.L). Publisher Copyright: © 2022 The Author(s)

PY - 2023/1

Y1 - 2023/1

N2 - Recent work has established associations between elevated p21, the accumulation of senescent cells, and skeletal muscle dysfunction in mice and humans. Using a mouse model of p21 overexpression (p21OE), we examined if p21 mechanistically contributes to cellular senescence and pathological features in skeletal muscle. We show that p21 induces several core properties of cellular senescence in skeletal muscle, including an altered transcriptome, DNA damage, mitochondrial dysfunction, and the senescence-associated secretory phenotype (SASP). Furthermore, p21OE mice exhibit manifestations of skeletal muscle pathology, such as atrophy, fibrosis, and impaired physical function when compared to age-matched controls. These findings suggest p21 alone is sufficient to drive a cellular senescence program and reveal a novel source of skeletal muscle loss and dysfunction.

AB - Recent work has established associations between elevated p21, the accumulation of senescent cells, and skeletal muscle dysfunction in mice and humans. Using a mouse model of p21 overexpression (p21OE), we examined if p21 mechanistically contributes to cellular senescence and pathological features in skeletal muscle. We show that p21 induces several core properties of cellular senescence in skeletal muscle, including an altered transcriptome, DNA damage, mitochondrial dysfunction, and the senescence-associated secretory phenotype (SASP). Furthermore, p21OE mice exhibit manifestations of skeletal muscle pathology, such as atrophy, fibrosis, and impaired physical function when compared to age-matched controls. These findings suggest p21 alone is sufficient to drive a cellular senescence program and reveal a novel source of skeletal muscle loss and dysfunction.

KW - Aging

KW - Cellular senescence

KW - DNA damage

KW - Fibrosis

KW - Physical function

KW - Sarcopenia

KW - Senescence-associated secretory phenotype

U2 - 10.1016/j.molmet.2022.101652

DO - 10.1016/j.molmet.2022.101652

M3 - Article

C2 - 36509362

AN - SCOPUS:85144500143

SN - 2212-8778

VL - 67

JO - Molecular metabolism

JF - Molecular metabolism

M1 - 101652

ER -

p21 induces a senescence program and skeletal muscle dysfunction

Abstract

Keywords

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