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A neuronal action of sirtuin 1 suppresses bone mass in young and aging mice
Na Luo, … , J. John Mann, Stavroula Kousteni
Na Luo, … , J. John Mann, Stavroula Kousteni
Published October 4, 2022
Citation Information: J Clin Invest. 2022;132(23):e152868. https://doi.org/10.1172/JCI152868.
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Research Article Bone Biology Neuroscience

A neuronal action of sirtuin 1 suppresses bone mass in young and aging mice

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Abstract

The various functions of the skeleton are influenced by extracellular cues, hormones, and neurotransmitters. One type of neuronal regulation favors bone mass accrual by inhibiting sympathetic nervous system (SNS) activity. This observation raises questions about the transcriptional mechanisms regulating catecholamine synthesis. Using a combination of genetic and pharmacological studies, we found that the histone deacetylase sirtuin 1 (SIRT1) is a transcriptional modulator of the neuronal control of bone mass. Neuronal SIRT1 reduced bone mass by increasing SNS signaling. SIRT1 did so by increasing expression of monoamine oxidase A (MAO-A), a SIRT1 target that reduces brain serotonin levels by inducing its catabolism and by suppressing tryptophan hydroxylase 2 (Tph2) expression and serotonin synthesis in the brain stem. SIRT1 upregulated brain catecholamine synthesis indirectly through serotonin, but did not directly affect dopamine β hydroxylase (Dbh) expression in the locus coeruleus. These results help us to understand skeletal changes associated with selective serotonin reuptake inhibitors (SSRIs) and may have implications for treating skeletal and metabolic diseases.

Authors

Na Luo, Ioanna Mosialou, Mattia Capulli, Brygida Bisikirska, Chyuan-Sheng Lin, Yung-yu Huang, Peter T. Shyu, X. Edward Guo, Aris Economides, J. John Mann, Stavroula Kousteni

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Figure 3

Decreased serotonin synthesis and increased Dbh and MAO-A expression in the brain of TgSirt1 mice.

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Decreased serotonin synthesis and increased Dbh and MAO-A expression in ...
(A) Tph2 expression levels in the brain stem (BS) of 3-month-old TgSirt1 mice (n = 5) versus WT controls (n = 5). (B) 5HT levels in brain stem of TgSirt1 mice (n = 6) versus WT controls (n = 4) measured by HPLC. (C) MAO-A expression levels in the rest of brain (ROB) of 3-month-old TgSirt1 mice (n = 4) versus WT controls (n = 4). (D) MAO-A activity (103 RLU/μg protein/h) in the hypothalamus, brain stem, and rest of brain of TgSirt1 mice treated with phenelzine (n = 5) versus vehicle controls (n = 5). (E) 5HT and 5-HIAA levels in brain stem and rest of brain of TgSirt1 mice treated with phenelzine (n = 5) versus vehicle controls (n = 5) measured by HPLC. (F) BV/TV (%); (G) N.Ob/T.Ar (/mm2); (H) BFR/BS (μm3/μm2/yr); and (I) Oc.S/BS (%) of 3-month-old TgSirt1 mice treated with phenelzine (n = 5) versus vehicle (n = 6) and WT controls (n = 5). (J) Representative images of spines from 3-month-old TgSirt1 mice treated with phenelzine versus vehicle and WT controls stained with von Kossa. (K) Dbh expression levels in midbrain (MB) of 3-month-old TgSirt1 mice (n = 5) versus WT controls (n = 5). (L) Tph2 expression levels in brain stem of 3-month-old Sirt1brain–/– mice (n = 4) versus Sirt1COIN/COIN controls (n = 4). (M) MAO-A expression levels in rest of brain of 3-month-old Sirt1brain–/– mice (n = 4) versus Sirt1COIN/COIN controls (n = 4). (N) Dbh expression levels in MB of 3-month-old Sirt1brain–/– mice (n = 4) versus Sirt1COIN/COIN controls (n = 4). Data are represented as mean ± SEM. (A–E and K–N) *P < 0.05, Student’s t test. (F–I) *P < 0.05, TgSirt1 mice treated with phenelzine versus vehicle by 1-way ANOVA.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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