Sulfur Amino Acid Supplementation Abrogates Protective Effects of Caloric Restriction for Enhancing Bone Marrow Regrowth Following Ionizing Radiation

Radiation therapy damages and depletes total bone marrow (BM) cellularity, compromising safety and limiting effective dosing. Aging also strains total BM and BM hematopoietic stem and progenitor cell (HSPC) renewal and function, resulting in multi-system defects. Interventions that preserve BM and B...

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Main Authors: Christopher Hine, J. Humberto Treviño-Villarreal, Pedro Mejia, Alban Longchamp, Lear E. Brace, Eylul Harputlugil, Sarah J. Mitchell, Jie Yang, Yihong Guan, Jaroslaw P. Maciejewski, Babal K. Jha, James R. Mitchell
Format: Article
Language:English
Published: MDPI AG 2022-04-01
Series:Nutrients
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Online Access:https://www.mdpi.com/2072-6643/14/7/1529
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author Christopher Hine
J. Humberto Treviño-Villarreal
Pedro Mejia
Alban Longchamp
Lear E. Brace
Eylul Harputlugil
Sarah J. Mitchell
Jie Yang
Yihong Guan
Jaroslaw P. Maciejewski
Babal K. Jha
James R. Mitchell
author_facet Christopher Hine
J. Humberto Treviño-Villarreal
Pedro Mejia
Alban Longchamp
Lear E. Brace
Eylul Harputlugil
Sarah J. Mitchell
Jie Yang
Yihong Guan
Jaroslaw P. Maciejewski
Babal K. Jha
James R. Mitchell
author_sort Christopher Hine
collection DOAJ
description Radiation therapy damages and depletes total bone marrow (BM) cellularity, compromising safety and limiting effective dosing. Aging also strains total BM and BM hematopoietic stem and progenitor cell (HSPC) renewal and function, resulting in multi-system defects. Interventions that preserve BM and BM HSPC homeostasis thus have potential clinical significance. Here, we report that 50% calorie restriction (CR) for 7-days or fasting for 3-days prior to irradiation improved mouse BM regrowth in the days and weeks post irradiation. Specifically, one week of 50% CR ameliorated loss of total BM cellularity post irradiation compared to <i>ad libitum</i>-fed controls. CR-mediated BM protection was abrogated by dietary sulfur amino acid (i.e., cysteine, methionine) supplementation or pharmacological inhibition of sulfur amino acid metabolizing and hydrogen sulfide (H<sub>2</sub>S) producing enzymes. Up to 2-fold increased proliferative capacity of <i>ex vivo</i>-irradiated BM isolated from food restricted mice relative to control mice indicates cell autonomy of the protective effect. Pretreatment with H<sub>2</sub>S <i>in vitro</i> was sufficient to preserve proliferative capacity by over 50% compared to non-treated cells in <i>ex vivo</i>-irradiated BM and BM HSPCs. The exogenous addition of H<sub>2</sub>S inhibited Ten eleven translocation 2 (TET2) activity <i>in vitro</i>, thus providing a potential mechanism of action. Short-term CR or fasting therefore offers BM radioprotection and promotes regrowth in part via altered sulfur amino acid metabolism and H<sub>2</sub>S generation, with translational implications for radiation treatment and aging.
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spelling doaj.art-4127a28000664bfbbaf68c79a9a0c7032023-11-30T23:49:34ZengMDPI AGNutrients2072-66432022-04-01147152910.3390/nu14071529Sulfur Amino Acid Supplementation Abrogates Protective Effects of Caloric Restriction for Enhancing Bone Marrow Regrowth Following Ionizing RadiationChristopher Hine0J. Humberto Treviño-Villarreal1Pedro Mejia2Alban Longchamp3Lear E. Brace4Eylul Harputlugil5Sarah J. Mitchell6Jie Yang7Yihong Guan8Jaroslaw P. Maciejewski9Babal K. Jha10James R. Mitchell11Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USADepartment of Molecular Metabolism (Formally Genetics and Complex Diseases), Harvard T.H. Chan School of Public Health, Boston, MA 02115, USADepartment of Molecular Metabolism (Formally Genetics and Complex Diseases), Harvard T.H. Chan School of Public Health, Boston, MA 02115, USADepartment of Molecular Metabolism (Formally Genetics and Complex Diseases), Harvard T.H. Chan School of Public Health, Boston, MA 02115, USADepartment of Molecular Metabolism (Formally Genetics and Complex Diseases), Harvard T.H. Chan School of Public Health, Boston, MA 02115, USADepartment of Molecular Metabolism (Formally Genetics and Complex Diseases), Harvard T.H. Chan School of Public Health, Boston, MA 02115, USADepartment of Molecular Metabolism (Formally Genetics and Complex Diseases), Harvard T.H. Chan School of Public Health, Boston, MA 02115, USADepartment of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USADepartment of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USADepartment of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USADepartment of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USADepartment of Molecular Metabolism (Formally Genetics and Complex Diseases), Harvard T.H. Chan School of Public Health, Boston, MA 02115, USARadiation therapy damages and depletes total bone marrow (BM) cellularity, compromising safety and limiting effective dosing. Aging also strains total BM and BM hematopoietic stem and progenitor cell (HSPC) renewal and function, resulting in multi-system defects. Interventions that preserve BM and BM HSPC homeostasis thus have potential clinical significance. Here, we report that 50% calorie restriction (CR) for 7-days or fasting for 3-days prior to irradiation improved mouse BM regrowth in the days and weeks post irradiation. Specifically, one week of 50% CR ameliorated loss of total BM cellularity post irradiation compared to <i>ad libitum</i>-fed controls. CR-mediated BM protection was abrogated by dietary sulfur amino acid (i.e., cysteine, methionine) supplementation or pharmacological inhibition of sulfur amino acid metabolizing and hydrogen sulfide (H<sub>2</sub>S) producing enzymes. Up to 2-fold increased proliferative capacity of <i>ex vivo</i>-irradiated BM isolated from food restricted mice relative to control mice indicates cell autonomy of the protective effect. Pretreatment with H<sub>2</sub>S <i>in vitro</i> was sufficient to preserve proliferative capacity by over 50% compared to non-treated cells in <i>ex vivo</i>-irradiated BM and BM HSPCs. The exogenous addition of H<sub>2</sub>S inhibited Ten eleven translocation 2 (TET2) activity <i>in vitro</i>, thus providing a potential mechanism of action. Short-term CR or fasting therefore offers BM radioprotection and promotes regrowth in part via altered sulfur amino acid metabolism and H<sub>2</sub>S generation, with translational implications for radiation treatment and aging.https://www.mdpi.com/2072-6643/14/7/1529caloric restriction (CR)fastingbone marrowradioprotectioncystathionine γ-lyase (CGL)hydrogen sulfide (H<sub>2</sub>S)
spellingShingle Christopher Hine
J. Humberto Treviño-Villarreal
Pedro Mejia
Alban Longchamp
Lear E. Brace
Eylul Harputlugil
Sarah J. Mitchell
Jie Yang
Yihong Guan
Jaroslaw P. Maciejewski
Babal K. Jha
James R. Mitchell
Sulfur Amino Acid Supplementation Abrogates Protective Effects of Caloric Restriction for Enhancing Bone Marrow Regrowth Following Ionizing Radiation
Nutrients
caloric restriction (CR)
fasting
bone marrow
radioprotection
cystathionine γ-lyase (CGL)
hydrogen sulfide (H<sub>2</sub>S)
title Sulfur Amino Acid Supplementation Abrogates Protective Effects of Caloric Restriction for Enhancing Bone Marrow Regrowth Following Ionizing Radiation
title_full Sulfur Amino Acid Supplementation Abrogates Protective Effects of Caloric Restriction for Enhancing Bone Marrow Regrowth Following Ionizing Radiation
title_fullStr Sulfur Amino Acid Supplementation Abrogates Protective Effects of Caloric Restriction for Enhancing Bone Marrow Regrowth Following Ionizing Radiation
title_full_unstemmed Sulfur Amino Acid Supplementation Abrogates Protective Effects of Caloric Restriction for Enhancing Bone Marrow Regrowth Following Ionizing Radiation
title_short Sulfur Amino Acid Supplementation Abrogates Protective Effects of Caloric Restriction for Enhancing Bone Marrow Regrowth Following Ionizing Radiation
title_sort sulfur amino acid supplementation abrogates protective effects of caloric restriction for enhancing bone marrow regrowth following ionizing radiation
topic caloric restriction (CR)
fasting
bone marrow
radioprotection
cystathionine γ-lyase (CGL)
hydrogen sulfide (H<sub>2</sub>S)
url https://www.mdpi.com/2072-6643/14/7/1529
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