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Age-associated NF-?B signaling in myofibers alters the satellite cell niche and re-strains muscle stem cell function.

ABSTRACT: Skeletal muscle is a highly regenerative tissue, but muscle repair potential is increasingly compromised with advancing age. In this study, we demonstrate that increased NF-?B activity in aged muscle fibers contributes to diminished myogenic potential of their associated satellite cells. We further examine the impact of genetic modulation of NF-?B signaling in muscle satellite cells or myofibers on recovery after damage. These studies reveal that NF-?B activity in differentiated myofibers is sufficient to drive dysfunction of muscle regenerative cells via cell-non-autonomous mechanisms. Inhibition of NF-?B, or its downstream target Phospholipase A2, in myofibers rescued muscle regenerative potential in aged muscle. Moreover, systemic administration of sodium salicylate, an FDA-approved NF-?B inhibitor, decreased inflammatory gene expression and improved repair in aged muscle. Together, these studies identify a unique NF-?B regulated, non-cell autonomous mechanism by which stem cell function is linked to lipid signaling and homeostasis, and provide important new targets to stimulate muscle repair in aged individuals.

SUBMITTER: Oh J

PROVIDER: S-EPMC5191876 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Age-associated NF-κB signaling in myofibers alters the satellite cell niche and re-strains muscle stem cell function.

Oh Juhyun J Sinha Indranil I Tan Kah Yong KY Rosner Bernard B Dreyfuss Jonathan M JM Gjata Ornela O Tran Peter P Shoelson Steven E SE Wagers Amy J AJ

Aging 20161101 11

Skeletal muscle is a highly regenerative tissue, but muscle repair potential is increasingly compromised with advancing age. In this study, we demonstrate that increased NF-κB activity in aged muscle fibers contributes to diminished myogenic potential of their associated satellite cells. We further examine the impact of genetic modulation of NF-κB signaling in muscle satellite cells or myofibers on recovery after damage. These studies reveal that NF-κB activity in differentiated myofibers is suf ...[more]

PMID: 27852976

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Project description:Arsenic is a contaminant found worldwide in drinking water and food. Epidemiological studies have correlated arsenic exposure with reduced weight gain and improper muscular development, while in vitro studies show that arsenic exposure impairs myogenic differentiation. The purpose of this study was to use Fundulus heteroclitus or killifish as a model organism to determine if embryonic-only arsenic exposure permanently reduces the number or function of muscle satellite cells. Killifish embryos were exposed to 0, 50, 200, or 800 ppb arsenite (AsIII) until hatching, and then juvenile fish were raised in clean water. At 28, 40, and 52 weeks after hatching, skeletal muscle injuries were induced by injecting cardiotoxin into the trunk of the fish just posterior to the dorsal fin. Muscle sections were collected at 0, 3 and 10 days post-injury. Collagen levels were used to assess muscle tissue damage and recovery, while levels of proliferating cell nuclear antigen (PCNA) and myogenin were quantified to compare proliferating cells and newly formed myoblasts. At 28 weeks of age, baseline collagen levels were 105% and 112% greater in 200 and 800 ppb groups, respectively, and at 52 weeks of age, were 58% higher than controls in the 200 ppb fish. After cardiotoxin injury, collagen levels tend to increase to a greater extent and take longer to resolve in the arsenic exposed fish. The number of baseline PCNA(+) cells were 48-216% greater in 800 ppb exposed fish compared to controls, depending on the week examined. However, following cardiotoxin injury, PCNA is reduced at 28 weeks in 200 and 800 ppb fish at day 3 during the recovery period. By 52 weeks, there are significant reductions in PCNA in all exposure groups at day 3 of the recovery period. Based on these results, embryonic arsenic exposure increases baseline collagen levels and PCNA(+) cells in skeletal muscle. However, when these fish are challenged with a muscle injury, the proliferation and differentiation of satellite cells into myogenic precursors is impaired and instead, the fish appear to be favoring a fibrotic resolution to the injury.

Dataset Information

Age-associated NF-?B signaling in myofibers alters the satellite cell niche and re-strains muscle stem cell function.

Publications

Age-associated NF-κB signaling in myofibers alters the satellite cell niche and re-strains muscle stem cell function.

Similar Datasets

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