Skeletal muscle RBM3 expression is associated with extended lifespan in Ames Dwarf and calorie restricted mice

Zachary R. Hettinger; Amy L. Confides; Peter W. Vanderklish; Silvana Sidhom; Michal M. Masternak; Esther E. Dupont-Versteegden

doi:10.1016/j.exger.2020.111214

Skeletal muscle RBM3 expression is associated with extended lifespan in Ames Dwarf and calorie restricted mice

Zachary R. Hettinger, Amy L. Confides, Peter W. Vanderklish, Silvana Sidhom, Michal M. Masternak, Esther E. Dupont-Versteegden

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

7 Scopus citations

Abstract

RNA binding protein motif 3 (RBM3) is an RNA-binding and cold shock protein that protects myoblasts and promotes skeletal muscle hypertrophy by enhancing mRNA stability and translation. Muscle size is decreased during aging; however, it is typically delayed in models of extended lifespan such as the long-lived Ames Dwarf (df/df) mice and calorie restricted (CR) animals compared to age-matched controls. In light of the protective and anabolic effects of RBM3 in muscle, we hypothesized that RBM3 expression is higher in long-lived animal models. Young and old df/df mice, and adult and old UM-HET3 CR mice were used to test this hypothesis. Gastrocnemius muscles were harvested and protein was isolated for RBM3 protein measurements. CR induced a 1.7 and 1.3-fold elevation in RBM3 protein abundance compared to adult and old male mice fed ad libitum (AL) diets, respectively; this effect was shared between males and females. Ames dwarfism induced a 4.6 and 2.7-fold elevation in RBM3 protein abundance in young and old df/df mice compared to normal control littermates, respectively. In contrast, there was an age-associated decrease in cold-inducible RNA-binding protein (CIRP), suggesting these effects are specific for RBM3. Lastly, there was an age-associated increase in RNA degradation marker decapping enzyme 2 (DCP2) in UM-HET3 mice that was mitigated by CR. These results show that muscle RBM3 expression is correlated with extended lifespan in both df/df and CR animals. Identifying how RBM3 exerts protective effects in muscle may yield new insights into healthy aging of skeletal muscle.

Original language	English
Article number	111214
Journal	Experimental Gerontology
Volume	146
DOIs	https://doi.org/10.1016/j.exger.2020.111214
State	Published - Apr 2021

Bibliographical note

Publisher Copyright:
© 2020 Elsevier Inc.

Funding

Funding for this study was received from NIH/NIA for MM (R56AG061414, R03AG059846, R15AG059190) and for the UM-HET mice to Dr. Richard Miller (P30-AG024824). In addition, funds were received from the Endowed Professor in Health Sciences at the University of Kentucky.Funding from the Endowed Professor in Health Sciences for ZH. NIH/NIA funding for MM (R56AG061414, RO3AG059846). We would like to thank Drs. Susan Brooks and Richard Miller (University of Michigan) for the kind gift of gastrocnemius muscles from UM-HET3 mice through the Pepper Center's Core Facility for Aged Rodents (P30-AG024824). All procedures and conditions for animal care were approved by the University of Michigan Committee on Use and Care of Animals and met standards for animal housing as described in the Animal Welfare Act, the Guide for Care and Use of Laboratory Animals, and the Guide for the Care and Use of Agricultural Animals in Agricultural Research and Teaching, along with the Laboratory Animal Care and Use Committee (LACUC) at the Southern Illinois University School of Medicine. All data and information of materials will be made available upon reasonable request with the corresponding author. All animal care procedures for calorie restricted animals were performed at the University of Michigan. All animal care procedures for Ames Dwarf mice were performed at Southern Illinois University. All analyses of skeletal muscle immunoblotting were performed at the University of Kentucky. All analyses of hippocampus immunoblotting were performed at Scripps Research Institute. Z.H. was responsible for drafting and revising the manuscript. Z.H. A.C. P.V. and S.S. were responsible for data acquisition, analysis, and interpretation. E.D.V. M.M, and P.V. were responsible for conception and design of the experiments, acquisition of data, interpretation of results, and critically revising the manuscript. All authors have approved the final version of the manuscript and agree to be held accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed. None. Funding for this study was received from NIH / NIA for MM ( R56AG061414 , R03AG059846 , R15AG059190 ) and for the UM-HET mice to Dr. Richard Miller ( P30-AG024824 ). In addition, funds were received from the Endowed Professor in Health Sciences at the University of Kentucky .

Funders	Funder number
Guide for the Care
Guide for the Care
NIA/NIH	RO3AG059846
National Institutes of Health (NIH)
National Institute on Aging	R56AG061414, P30-AG024824, R03AG059846, R15AG059190
Michigan Retirement Research Center, University of Michigan
University of Kentucky
Southern Illinois University School of Medicine

Keywords

Aging
Longevity
RBM3
RNA
RNA-binding proteins
Skeletal muscle

ASJC Scopus subject areas

Biochemistry
Aging
Molecular Biology
Genetics
Endocrinology
Cell Biology

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10.1016/j.exger.2020.111214

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@article{b25c960db53a4abcb13cb70c6452cb3d,

title = "Skeletal muscle RBM3 expression is associated with extended lifespan in Ames Dwarf and calorie restricted mice",

abstract = "RNA binding protein motif 3 (RBM3) is an RNA-binding and cold shock protein that protects myoblasts and promotes skeletal muscle hypertrophy by enhancing mRNA stability and translation. Muscle size is decreased during aging; however, it is typically delayed in models of extended lifespan such as the long-lived Ames Dwarf (df/df) mice and calorie restricted (CR) animals compared to age-matched controls. In light of the protective and anabolic effects of RBM3 in muscle, we hypothesized that RBM3 expression is higher in long-lived animal models. Young and old df/df mice, and adult and old UM-HET3 CR mice were used to test this hypothesis. Gastrocnemius muscles were harvested and protein was isolated for RBM3 protein measurements. CR induced a 1.7 and 1.3-fold elevation in RBM3 protein abundance compared to adult and old male mice fed ad libitum (AL) diets, respectively; this effect was shared between males and females. Ames dwarfism induced a 4.6 and 2.7-fold elevation in RBM3 protein abundance in young and old df/df mice compared to normal control littermates, respectively. In contrast, there was an age-associated decrease in cold-inducible RNA-binding protein (CIRP), suggesting these effects are specific for RBM3. Lastly, there was an age-associated increase in RNA degradation marker decapping enzyme 2 (DCP2) in UM-HET3 mice that was mitigated by CR. These results show that muscle RBM3 expression is correlated with extended lifespan in both df/df and CR animals. Identifying how RBM3 exerts protective effects in muscle may yield new insights into healthy aging of skeletal muscle.",

keywords = "Aging, Longevity, RBM3, RNA, RNA-binding proteins, Skeletal muscle",

author = "Hettinger, {Zachary R.} and Confides, {Amy L.} and Vanderklish, {Peter W.} and Silvana Sidhom and Masternak, {Michal M.} and Dupont-Versteegden, {Esther E.}",

note = "Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2021",

month = apr,

doi = "10.1016/j.exger.2020.111214",

language = "English",

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AU - Hettinger, Zachary R.

AU - Confides, Amy L.

AU - Vanderklish, Peter W.

AU - Sidhom, Silvana

AU - Masternak, Michal M.

AU - Dupont-Versteegden, Esther E.

PY - 2021/4

Y1 - 2021/4

N2 - RNA binding protein motif 3 (RBM3) is an RNA-binding and cold shock protein that protects myoblasts and promotes skeletal muscle hypertrophy by enhancing mRNA stability and translation. Muscle size is decreased during aging; however, it is typically delayed in models of extended lifespan such as the long-lived Ames Dwarf (df/df) mice and calorie restricted (CR) animals compared to age-matched controls. In light of the protective and anabolic effects of RBM3 in muscle, we hypothesized that RBM3 expression is higher in long-lived animal models. Young and old df/df mice, and adult and old UM-HET3 CR mice were used to test this hypothesis. Gastrocnemius muscles were harvested and protein was isolated for RBM3 protein measurements. CR induced a 1.7 and 1.3-fold elevation in RBM3 protein abundance compared to adult and old male mice fed ad libitum (AL) diets, respectively; this effect was shared between males and females. Ames dwarfism induced a 4.6 and 2.7-fold elevation in RBM3 protein abundance in young and old df/df mice compared to normal control littermates, respectively. In contrast, there was an age-associated decrease in cold-inducible RNA-binding protein (CIRP), suggesting these effects are specific for RBM3. Lastly, there was an age-associated increase in RNA degradation marker decapping enzyme 2 (DCP2) in UM-HET3 mice that was mitigated by CR. These results show that muscle RBM3 expression is correlated with extended lifespan in both df/df and CR animals. Identifying how RBM3 exerts protective effects in muscle may yield new insights into healthy aging of skeletal muscle.

AB - RNA binding protein motif 3 (RBM3) is an RNA-binding and cold shock protein that protects myoblasts and promotes skeletal muscle hypertrophy by enhancing mRNA stability and translation. Muscle size is decreased during aging; however, it is typically delayed in models of extended lifespan such as the long-lived Ames Dwarf (df/df) mice and calorie restricted (CR) animals compared to age-matched controls. In light of the protective and anabolic effects of RBM3 in muscle, we hypothesized that RBM3 expression is higher in long-lived animal models. Young and old df/df mice, and adult and old UM-HET3 CR mice were used to test this hypothesis. Gastrocnemius muscles were harvested and protein was isolated for RBM3 protein measurements. CR induced a 1.7 and 1.3-fold elevation in RBM3 protein abundance compared to adult and old male mice fed ad libitum (AL) diets, respectively; this effect was shared between males and females. Ames dwarfism induced a 4.6 and 2.7-fold elevation in RBM3 protein abundance in young and old df/df mice compared to normal control littermates, respectively. In contrast, there was an age-associated decrease in cold-inducible RNA-binding protein (CIRP), suggesting these effects are specific for RBM3. Lastly, there was an age-associated increase in RNA degradation marker decapping enzyme 2 (DCP2) in UM-HET3 mice that was mitigated by CR. These results show that muscle RBM3 expression is correlated with extended lifespan in both df/df and CR animals. Identifying how RBM3 exerts protective effects in muscle may yield new insights into healthy aging of skeletal muscle.

KW - Aging

KW - Longevity

KW - RBM3

KW - RNA

KW - RNA-binding proteins

KW - Skeletal muscle

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VL - 146

JO - Experimental Gerontology

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Skeletal muscle RBM3 expression is associated with extended lifespan in Ames Dwarf and calorie restricted mice

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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