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

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 5

Neuronal SIRT1 decreases bone mass by decreasing serotonin synthesis and enhancing its catabolism through its actions on serotonergic and MAO-A–expressing neurons.

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Neuronal SIRT1 decreases bone mass by decreasing serotonin synthesis and...
(A) Ucp1 expression in BAT of Sirt1Syn–/– mice (n = 7) versus controls (n = 7). (B) Expression of SNS target genes in long bone of Sirt1Syn–/– mice (n = 5) versus controls (n = 5). (C) Tph2 expression in brain stem of Sirt1Syn–/– mice (n = 7) versus controls (n = 7). (D) MAO-A expression and (E) MAO-A activity in rest of brain of Sirt1Syn–/– mice (n = 5) versus controls (n = 5). (F) Dbh expression in MB of Sirt1Syn–/– mice (n = 5) versus controls (n = 5). (G) Bche expression in hypothalamus of Sirt1Syn–/– mice (n = 6) versus controls (n = 6). (H) Ucp1 expression in BAT of Sirt1Sert–/– mice (n = 4) versus controls (n = 8). (I) Expression of SNS target genes in long bone of Sirt1Sert–/– mice (n = 4) versus controls (n = 4). (J) Tph2 expression in brain stem of Sirt1Sert–/– mice (n = 4) versus controls (n = 6). (K) MAO-A expression in rest of brain of Sirt1Sert–/– mice (n = 4) versus controls (n = 8). (L) MAO-A activity in rest of brain of Sirt1Sert–/– mice (n = 5) versus controls (n = 5). (M) Dbh expression in MB of Sirt1Sert–/– mice (n = 4) versus controls (n = 5). (N) Bche expression in hypothalamus of Sirt1Sert–/– mice(n = 4) versus controls (n = 4). (O) Ucp1 expression in BAT of Sirt1Dbh–/– mice (n = 5) versus controls (n = 5). (P) Expression of SNS target genes in long bone of Sirt1Dbh–/– mice (n = 5) versus controls (n = 5). (Q) Tph2 expression in brain stem of Sirt1Dbh–/– mice (n = 4) versus controls (n = 5). (R) MAO-A expression in rest of brain of Sirt1Dbh–/– mice (n = 4) versus controls (n = 5). (S) MAO-A activity in rest of brain of Sirt1Dbh–/– mice (n = 5) versus controls (n = 5). (T) Dbh expression in MB and (U) Bche expression in hypothalamus of Sirt1Dbh–/– (n = 4) versus controls (n = 5). Data are represented as mean ± SEM. *P < 0.05 versus Sirt1COIN/COIN by Student’s t test.