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Signaling Pathways that control muscle mass

sandri_group_fotoGroup leader Lab members:
  • Enrcio Berteggia (Postdoc)
  • Silvia Carino (Postdoc)
  • Luisa Coletto (Postdoc)
  • Francesca Lo Verso (PhD student)
  • Giulia Milan (Postdoc)
  • Vanina Romanello (Postdoc)
  • Roberta Sartori (Postdoc)
  • Ricardo Soares (PhD student)

 

Scientific activity:

Scientific Outline

Ageing sarcopenia as well as muscle loss in many other diseases including disuse, denervation, cancer, AIDS, diabetes, and cardiac failure are characterized by activation of different proteolytic systems for degradation of contractile proteins and organelle removal. Loss of muscle proteins can result in muscle atrophy and weakness that have significant clinical consequences. For instance age-dependent muscle wasting favour traumatic events, accident, fracture or illness which lead to aged person to become bed-ridden or  housebound, thus having a high mortality in the year following their accident. The signalling, which coordinates loss of proteins and organelle in mammalian cells including muscle fibers, are poorly understood. We recently demonstrated that the loss of muscle mass involves a common pattern of transcriptional changes, including induction of genes for protein degradation and decreased expression of various genes for growth-related and energy-yielding processes. This group of co-ordinately regulated genes have been termed atrophy-related genes. The two most induced genes were two novel muscle-specific ubiquitin ligases, atrogin-1/MAFbx and MuRF1. These enzymes are responsible for the increased protein degradation through the ubiquitin-proteasome system and are under FoxO and NFkB control. However the contribution of the other atrophy-related genes and the signalling that coordinates the atrophy program is still obscure.To counteract muscle weakness we need a better picture of the molecular events that activate the atrophy program. The focus of my lab is to: i) define the transcriptional regulation of the described atrophy-related genes and find new ones, ii) define the mechanisms of regulation at translational level for the described atrophy-related genes and for the new ones, iii) translate the findings obtained in animal models to human skeletal muscles.

sandri_image Autophagy and muscle degeneration.
Immunohistochemistry image (background) of Atg7-deficient Tibialis Anterior muscle depicts p62/SQSTM1 protein aggregates (green) in myofibers; nuclei are shown in blue. The cartoon (right inset) shows a lens that enlarges details within the muscle cells. The autophagy system is transformed into pacman videogame. Pacman destroys toxic proteins (the yellow dots in the videogame) and damaged/death organelles (ghosts) within the labyrinth of the cytoplasm of the myofiber. The “killing” of the autophagy system (the death pacman) causes accumulation of big and abnormal mitochondria (the giant ghosts) and formation of inclusion bodies that are constituted by aggregation of p62/SQSTM1 (green) and ubiquitinated (red) proteins. Image by Masiero et al. Cell Metabolism 2009, graphic by R. Zanini.

Funded by:

teleton_logo Telethon, Italy
tp7_logo_pic TP7 MYOAGE, EU
miur_logo_pic MIUR, Italy
unipd_logo University of Padova
afm_logo_pic AFM, France

Publications:

5 recent publications:

  1. Sandri M., Lin J., Handschin C., Yang W., Arany Z., Lecker S., Goldberg A.L., Spiegelman B.M. PGC-1 protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc Natl Acad Sci U S A.; 2006. 103(44):16260-5.
  2. Mammucari C, Milan G., Romanello V., Masiero E., Ruediger R., Del Piccolo P., Burden S.J., Di Lisi R., Sandri C., Zhao J., Goldberg A.L., Schiaffino S., Sandri M. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab. 2007 Dec;6(6):458-71.
  3. Sandri M. Signaling in muscle atrophy and hypertrophy. Physiology, 2008; 23:160-70
  4. Sartori R, Milan G, Patron M, Mammucari C, Blaauw B, Abraham R, Sandri M. SMAD2 and 3 transcription factors control muscle mass in adulthood. Am J Physiol Cell Physiol. 2009 Jun;296(6):C1248-57
  5. Masiero E, Agatea L, Mammucari C, Blaauw B, Loro E, Komatsu M, Metzger D, Reggiani C, Schiaffino S, Sandri M. Autophagy is required to mantain muscle mass. Cell Metab. 2009, Dec;10(6):507-15


    5 selected publications (all career):

    1. Sandri M, Minetti C, Pedemonte M, Carraro U. Apoptotic myonuclei in human Duchenne muscular dystrophy. Lab. Invest. 1998; 78: 1005-1016
    2. Dona M, Sandri M, Rossini K, Dall’Aica I, Podhorska-Okolow M, Carraro U. Functional in vivo gene transfer into the myofibers of adult skeletal muscle. Biochem. Bioph. Res. Com. 2003; 312(4): 1132-8.
    3. Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, Walsh K, Schiaffino S, Lecker SH, Goldberg AL. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell. 2004; 117, 399-412
    4. Dobrowolny G., Aucello M., Rizzato E., Beccafico S., Mammucari C., Boncompagni S., Belia S., Wannenes F., Nicoletti C., Del Prete Z., Rosenthal N., Molinaro M., Protasi F., Fano G., Sandri M., Musaro A. Skeletal muscle is a primary target of SOD1G93A -mediated toxicity. Cell Metab. 2008 Nov; 8(5): 425-436.
    5. Mammucari C., Schiaffino S., Sandri M. Downstream of Akt: FoxO3 and mTOR in the regulation of autophagy in skeletal muscle. Autophagy. 2008;4(4):524-26.

     
    Ultimo aggiornamento Lunedì 13 Dicembre 2010 12:18