18/09/2009Seminrios do Laboratrio de Controle do Metabolismo

Factors that control the mass and function of skeletal muscleBASSEL-DUBY & OLSON. Annu Rev Biochem 75, 2006; NETTER. Atlas de anatomia humana, 2000.

http://www.cellsignal.com/reference/pathway/images/Insulin_Receptor.jpgINSULIN

SANDRI et al. Cell 117, 2004.

http://www.cellsignal.com/reference/pathway/images/Insulin_Receptor.jpgINSULIN

MAPK signaling pathwayshttp://www.babraham.ac.uk/images/research/signalling/cook/fig3a.jpg

RAMOS et al. Int J Biochem Cell Biol 40, 2008.

BUENO et al. EMBO 19(23): 6341-6350, 2000.MEK1 adenovirus induces anabolic status in cardiomyocytes

MEK1 transgenic mice develops cardiac hypertrophyBUENO et al. EMBO 19(23): 6341-6350, 2000.

Gastrocnemius treated for 2 weeks

(+ ERK)(+ Akt)(+ ral)

Examine the role of MAPK signaling in the maintenance of muscle mass in vitro and in vivo.

RESULTS & DISCUSSION

Inhibition of ERK1/2 signaling induced atrophy in myocytes

Transcripton of atrophic markers muscle-specific E3-ligases in MAPK inhibition-induced myocyteIt parallels the preferential degradation of contractile proteins

Cross talk between ERK and Akt signaling pathways

Similar effect on Soleus muscle

DISTINCT PROTEOLYTIC PATHWAYS DURING INHIBITION OF MAPK IN FAST AND SLOW MUSCLES

ConclusionsERK1/2 inhibition-induced atrophy is caused by 3 distinct, yet related signaling pathways:

Reduction of protein synthesis at the transcription ans translational levels;

Downregulation of Akt and its downstream kinases;

Increase of 26S proteasome activity and gene expression of MuRF-1 and Atrogin-1.

Clenbuterol increases the phosphorylation status of Akt and ERK p-Ser473 AktTotal Aktp-Thr202/Tyr204 ERK1p-Thr185/Tyr187 ERK2Total ERK1Total ERK2(p=0.07)(p=0.06)

GONALVES et al. Endocrinology, 2009.

Is cAMP responsible for phosphorylation status of Akt and ERK ?

Formoterol increases the phosphorylation status of Akt and ERK p-Ser473 Akt-tubulinap-Thr202/Tyr204 ERK1p-Thr185/Tyr187 ERK2Total ERK1Total ERK2

Obrigado!

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