MST1, a key player, in enhancing fast skeletal muscle atrophy.

Abstract

BACKGROUND:

Skeletal muscle undergoes rapid atrophy upon denervation and the underlying mechanisms are complicated. FOXO3a has been implicated as a major mediator of muscle atrophy, but how its subcellular location and activity is controlled during the pathogenesis of muscle atrophy remains largely unknown. MST1 (Mammalian Sterile 20-like kinase 1) is identified as a central component of the Hippo signaling pathway. MST1 has been shown to mediate phosphorylation of FOXO3a at Ser207. Whether this MST1-FOXO signaling cascade exerts any functional consequence on cellular homeostasis remains to be investigated.

RESULT:

We identified that MST1 kinase was expressed widely in skeletal muscles and was dramatically up-regulated in fast- but not slow-dominant skeletal muscles immediately following denervation. The results of our histological and biochemical studies demonstrated that deletion of MST1 significantly attenuated denervation-induced skeletal muscle wasting and decreased expression of Atrogin-1 and LC3 genes in fast-dominant skeletal muscles from three- to five-month-old adult mice. Further studies indicated that MST1, but not MST2, remarkably increased FOXO3a phosphorylation level at Ser207 and promoted its nuclear translocation in atrophic fast-dominant muscles.

CONCLUSIONS:

We have established that MST1 kinase plays an important role in regulating denervation-induced skeletal muscle atrophy. During the early stage of muscle atrophy, the up-regulated MST1 kinase promoted progression of neurogenic atrophy in fast-dominant skeletal muscles through activation of FOXO3a transcription factors.

• Authors: Bin Wei, Wen Dui, Dong Liu, Yan Xing, Zengqiang Yuan, Guangju Ji
• Journal: BMC biology (BMC Biol) Vol. 11 Pg. 12 (Feb 01 2013) ISSN: 1741-7007 [Electronic] England
• PMID: 23374633 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Forkhead Box Protein O3
• Forkhead Transcription Factors
• FoxO3 protein, mouse
• Muscle Proteins
• Fbxo32 protein, mouse
• SKP Cullin F-Box Protein Ligases
• Stk4 protein, mouse
• Protein Serine-Threonine Kinases

Topics

• Animals
• Animals, Newborn
• Forkhead Box Protein O3
• Forkhead Transcription Factors (metabolism)
• Mice
• Muscle Proteins (genetics)
• Muscle, Skeletal (enzymology, physiopathology)
• Muscular Atrophy (enzymology, physiopathology)
• Phosphorylation
• Protein Serine-Threonine Kinases (metabolism, physiology)
• SKP Cullin F-Box Protein Ligases (genetics)
• Signal Transduction
• Transcription, Genetic
• Up-Regulation