Secreted frizzled related protein 1 (Sfrp1) and Wnt signaling in innervated and denervated skeletal muscle

Svensson, Anna; Norrby, Marlene; Libelius, Rolf; Tågerud, Sven

doi:10.1007/s10735-008-9169-y

Cited by 14 publications

(14 citation statements)

References 33 publications

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“…Similarly, no decreased phosphorylation of GSK-3β (S9) was observed in atrophic denervated anterior tibial muscle as also reported previously [56]. Increased levels of Akt total protein and phosphorylated Akt were also recently reported in atrophic mouse muscles 2 weeks following denervation [37].…”

Section: Discussionsupporting

confidence: 82%

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Akt (protein kinase B) isoform phosphorylation and signaling downstream of mTOR (mammalian target of rapamycin) in denervated atrophic and hypertrophic mouse skeletal muscle

Norrby¹,

Evertsson²,

Fjällström³

et al. 2012

JMS

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BackgroundThe present study examines the hypothesis that Akt (protein kinase B)/mTOR (mammalian target of rapamycin) signaling is increased in hypertrophic and decreased in atrophic denervated muscle. Protein expression and phosphorylation of Akt1, Akt2, glycogen synthase kinase-3beta (GSK-3beta), eukaryotic initiation factor 4E binding protein 1 (4EBP1), 70 kD ribosomal protein S6 kinase (p70S6K1) and ribosomal protein S6 (rpS6) were examined in six-days denervated mouse anterior tibial (atrophic) and hemidiaphragm (hypertrophic) muscles.ResultsIn denervated hypertrophic muscle expression of total Akt1, Akt2, GSK-3beta, p70S6K1 and rpS6 proteins increased 2–10 fold whereas total 4EBP1 protein remained unaltered. In denervated atrophic muscle Akt1 and Akt2 total protein increased 2–16 fold. A small increase in expression of total rpS6 protein was also observed with no apparent changes in levels of total GSK-3beta, 4EBP1 or p70S6K1 proteins. The level of phosphorylated proteins increased 3–13 fold for all the proteins in hypertrophic denervated muscle. No significant changes in phosphorylated Akt1 or GSK-3beta were detected in atrophic denervated muscle. The phosphorylation levels of Akt2, 4EBP1, p70S6K1 and rpS6 were increased 2–18 fold in atrophic denervated muscle.ConclusionsThe results are consistent with increased Akt/mTOR signaling in hypertrophic skeletal muscle. Decreased levels of phosphorylated Akt (S473/S474) were not observed in denervated atrophic muscle and results downstream of mTOR indicate increased protein synthesis in denervated atrophic anterior tibial muscle as well as in denervated hypertrophic hemidiaphragm muscle. Increased protein degradation, rather than decreased protein synthesis, is likely to be responsible for the loss of muscle mass in denervated atrophic muscles.

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Section: Discussionsupporting

confidence: 82%

“…Increased expression of phosphorylated p70S6K1 and 4EBP1 proteins in denervated rat hemidiaphragm muscle has been reported previously [54] as has increased rpS6 phosphorylation [55] and increased phosphorylation of GSK-3β [56]. …”

Section: Discussionmentioning

confidence: 59%

Akt (protein kinase B) isoform phosphorylation and signaling downstream of mTOR (mammalian target of rapamycin) in denervated atrophic and hypertrophic mouse skeletal muscle

Norrby¹,

Evertsson²,

Fjällström³

et al. 2012

JMS

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“…Similarly, other intracellular Wnt signaling components, such as Dvl and casein kinase 2, regulate AChR clustering in cultured myotubes2122. In general, the strictly regulated expression of secreted antagonists including Dickkopf (Dkk) and secreted frizzled-related protein (Sfrps) and agonists such as R-spondins (Rspos) and Norrin enable the fine spatiotemporal modulation of Wnt signaling2324. For example, the Wnt antagonist Sfrp1 is induced by denervation at rat NMJs, and it suppresses Wnt signaling to disperse AChR clusters24.…”

mentioning

confidence: 99%

“…In general, the strictly regulated expression of secreted antagonists including Dickkopf (Dkk) and secreted frizzled-related protein (Sfrps) and agonists such as R-spondins (Rspos) and Norrin enable the fine spatiotemporal modulation of Wnt signaling2324. For example, the Wnt antagonist Sfrp1 is induced by denervation at rat NMJs, and it suppresses Wnt signaling to disperse AChR clusters24. However, no agonist of the Wnt signaling pathway is known to work on the NMJ formation.…”

mentioning

confidence: 99%

R-spondin 2 promotes acetylcholine receptor clustering at the neuromuscular junction via Lgr5

Nakashima

Ohkawara

Ishigaki

et al. 2016

Sci Rep

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At the neuromuscular junction (NMJ), acetylcholine receptor (AChR) clustering is mediated by spinal motor neuron (SMN)-derived agrin and its receptors on the muscle, the low-density lipoprotein receptor-related protein 4 (LRP4) and muscle-specific receptor tyrosine kinase (MuSK). Additionally, AChR clustering is mediated by the components of the Wnt pathway. Laser capture microdissection of SMNs revealed that a secreted activator of Wnt signaling, R-spondin 2 (Rspo2), is highly expressed in SMNs. We found that Rspo2 is enriched at the NMJ, and that Rspo2 induces MuSK phosphorylation and AChR clustering. Rspo2 requires Wnt ligands, but not agrin, for promoting AChR clustering in cultured myotubes. Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5), an Rspo2 receptor, is also accumulated at the NMJ, and is associated with MuSK via LRP4. Lgr5 is required for Rspo2-mediated AChR clustering in myotubes. In Rspo2-knockout mice, the number and density of AChRs at the NMJ are reduced. The Rspo2-knockout diaphragm has an altered ultrastructure with widened synaptic clefts and sparse synaptic vesicles. Frequency of miniature endplate currents is markedly reduced in Rspo2-knockout mice. To conclude, we demonstrate that Rspo2 and its receptor Lgr5 are Wnt-dependent and agrin-independent regulators of AChR clustering at the NMJ.

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“…These mutants also had a reduction in evoked release, defects in short-term plasticity, as well as calcium sensitivity 32 . Interestingly, SFRPs are present in muscles, localize to the NMJ and are upregulated upon denervation 38 , which raises the possibility that WNT signalling might mediate these β-catenin-dependent processes 32 .…”

Section: Wnt Signalling At the Vertebrate Nmjmentioning

confidence: 99%

WNTs tune up the neuromuscular junction

Korkut

Budnik

2009

Nat Rev Neurosci

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Although WNTs have been long thought of as regulators of cell fate, recent studies highlight their involvement in crucial aspects of synaptic development in the nervous system. Particularly compelling are recent studies of the neuromuscular junction in nematodes, insects, fish and mammals. These studies place WNTs as major determinants of synapse differentiation and neurotransmitter receptor clustering.

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Secreted frizzled related protein 1 (Sfrp1) and Wnt signaling in innervated and denervated skeletal muscle

Cited by 14 publications

References 33 publications

Akt (protein kinase B) isoform phosphorylation and signaling downstream of mTOR (mammalian target of rapamycin) in denervated atrophic and hypertrophic mouse skeletal muscle

Akt (protein kinase B) isoform phosphorylation and signaling downstream of mTOR (mammalian target of rapamycin) in denervated atrophic and hypertrophic mouse skeletal muscle

R-spondin 2 promotes acetylcholine receptor clustering at the neuromuscular junction via Lgr5

WNTs tune up the neuromuscular junction

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