PMID- 28122601
OWN - NLM
STAT- MEDLINE
DCOM- 20180326
LR  - 20211204
IS  - 2044-5040 (Electronic)
IS  - 2044-5040 (Linking)
VI  - 7
IP  - 1
DP  - 2017 Jan 25
TI  - Inhibition of Stat3 signaling ameliorates atrophy of the soleus muscles in mice 
      lacking the vitamin D receptor.
PG  - 2
LID - 10.1186/s13395-017-0121-2 [doi]
LID - 2
AB  - BACKGROUND: Although skeletal muscle wasting has long been observed as a clinical 
      outcome of impaired vitamin D signaling, precise molecular mechanisms that 
      mediate the loss of muscle mass in the absence of vitamin D signaling are less 
      clear. To determine the molecular consequences of vitamin D signaling, we 
      analyzed the role of signal transducer and activator of transcription 3 (Stat3) 
      signaling, a known contributor to various muscle wasting pathologies, in skeletal 
      muscles. METHODS: We isolated soleus (slow) and tibialis anterior (fast) muscles 
      from mice lacking the vitamin D receptor (VDR(-/-)) and used western blot 
      analysis, quantitative RTPCR, and pharmacological intervention to analyze muscle 
      atrophy in VDR(-/-) mice. RESULTS: We found that slow and fast subsets of muscles 
      of the VDR(-/-) mice displayed elevated levels of phosphorylated Stat3 
      accompanied by an increase in Myostatin expression and signaling. Consequently, 
      we observed reduced activity of mammalian target of rapamycin (mTOR) signaling 
      components, ribosomal S6 kinase (p70S6K) and ribosomal S6 protein (rpS6), that 
      regulate protein synthesis and cell size, respectively. Concomitantly, we 
      observed an increase in atrophy regulators and a block in autophagic gene 
      expression. An examination of the upstream regulation of Stat3 levels in VDR(-/-) 
      muscles revealed an increase in IL-6 protein expression in the soleus, but not in 
      the tibialis anterior muscles. To investigate the involvement of satellite cells 
      (SCs) in atrophy in VDR(-/-) mice, we found that there was no significant deficit 
      in SC numbers in VDR(-/-) muscles compared to the wild type. Unlike its 
      expression within VDR(-/-) fibers, Myostatin levels in VDR(-/-) SCs from bulk 
      muscles were similar to those of wild type. However, VDR(-/-) SCs induced to 
      differentiate in culture displayed increased p-Stat3 signaling and Myostatin 
      expression. Finally, VDR(-/-) mice injected with a Stat3 inhibitor displayed 
      reduced Myostatin expression and function and restored active p70S6K and rpS6 
      levels, resulting in an amelioration of loss of muscle mass in the soleus 
      muscles. CONCLUSIONS: The loss of muscle mass in slow muscles in the absence of 
      vitamin D signaling is due to elevated levels of phosphorylated Stat3 that leads 
      to an increase in Myostatin signaling, which in turn decreases protein synthesis 
      and fiber size through the phosphorylation of p70S6K and rpS6, respectively.
FAU - Gopinath, Suchitra D
AU  - Gopinath SD
AD  - Translational Health Science and Technology Institute (THSTI), NCR Biotech 
      Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, PO box #04, 
      Faridabad, 121001, India. sgopinath@thsti.res.in.
LA  - eng
PT  - Journal Article
DEP - 20170125
PL  - England
TA  - Skelet Muscle
JT  - Skeletal muscle
JID - 101561193
RN  - 0 (Myostatin)
RN  - 0 (Receptors, Calcitriol)
RN  - 0 (Ribosomal Protein S6)
RN  - 0 (STAT3 Transcription Factor)
RN  - 1406-16-2 (Vitamin D)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - Mice
MH  - Muscle, Skeletal/*metabolism/pathology
MH  - Muscular Atrophy/genetics/*metabolism
MH  - Myostatin/genetics/metabolism
MH  - Receptors, Calcitriol/genetics/*metabolism
MH  - Ribosomal Protein S6/metabolism
MH  - Ribosomal Protein S6 Kinases/metabolism
MH  - STAT3 Transcription Factor/*metabolism
MH  - *Signal Transduction
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Vitamin D/metabolism
PMC - PMC5264327
OTO - NOTNLM
OT  - Atrophy
OT  - Myostatin
OT  - Satellite cells
OT  - Skeletal muscle
OT  - Soleus
OT  - Tibialis anterior
OT  - p-70S6K
OT  - p-Stat3
OT  - p-rpS6
EDAT- 2017/01/27 06:00
MHDA- 2018/03/27 06:00
PMCR- 2017/01/25
CRDT- 2017/01/27 06:00
PHST- 2016/10/04 00:00 [received]
PHST- 2017/01/13 00:00 [accepted]
PHST- 2017/01/27 06:00 [entrez]
PHST- 2017/01/27 06:00 [pubmed]
PHST- 2018/03/27 06:00 [medline]
PHST- 2017/01/25 00:00 [pmc-release]
AID - 10.1186/s13395-017-0121-2 [pii]
AID - 121 [pii]
AID - 10.1186/s13395-017-0121-2 [doi]
PST - epublish
SO  - Skelet Muscle. 2017 Jan 25;7(1):2. doi: 10.1186/s13395-017-0121-2.