Which are the signals regulating adult skeletal muscle growth and function?
How are these signals regulated by exercise?
Adult skeletal muscle is an extremely plastic tissue, rapidly modifying its size and function responding to changes in demands. In the lab we are focusing our attention on the intracellular signaling pathways regulating increases in both mass and function of adult skeletal muscle. Considering the significant problems which arise during aging, disuse and numerous other pathologies like cancer cachexia, leading to muscle atrophy and weakness, together with the well-established beneficial effect of exercise, it is of fundamental importance to understand which pathways regulate muscle function and how these can be linked to exercise.
We have currently three lines of research in the lab:
– Dissecting the functional role of Akt-mTORC1 signaling in healthy and cachectic skeletal muscle
– Identifying the early signaling changes after exercise and how these are linked to muscle remodelling
– Determine the role of circadian rhythms on skeletal muscle function
We are using a wide range of physiological and molecular biological tools to address these questions in-vivo; electroporation, in-vivo and ex-vivo force measurements, various muscle-specific transgenic animals, basic molecular biology, ChIP-seq. Many national and international collaborators provide the expertise and technical support for specific parts of the projects.
Future research plans
Determining the importance of Akt-mTORC1 signaling in functional muscle growth
To prevent skeletal muscle atrophy leading to muscle weakness, as observed in neuromuscular diseases and many other pathological conditions, it is essential to get a better understanding of the signaling pathways which regulate skeletal muscle mass and function. Using a transgenic mouse in which the kinase Akt can be activated in skeletal muscle only, we showed that Akt activation is sufficient to lead to a significant skeletal muscle hypertrophy which is accompanied by an increase in muscle force (Blaauw et al., 2009). Akt has numerous downstream effectors which might contribute to increase muscle mass. We recently showed that one of its key downstream targets, S6K1, is not required for muscle growth, but is critical in increasing muscle force (Marabita et al., 2016). We are now examining the role played by Akt-mTORC1 signaling in various models of muscle growth, and how this pathway impinges on muscle dysfunction in specific pathologies, like cancer cachexia and disuse atrophy.
Early signaling changes linked to muscle remodelling after exercise
Skeletal muscle is an extremely plastic tissue. Adult skeletal muscle can undergo drastic alterations in muscle size and contractile properties when exposed to changes in activity levels, muscle loading or hormonal stimuli. Exercise is a very powerful way to modify muscle properties, leading either to an increase in the resistance to fatigue or in power output, depending on type of exercise performed. Surprisingly, how exercise is able to lead to long-lasting changes in gene transcription and subsequent improvements in muscle performance is not well understood. Using state-of-the-art quantitative phosphoproteomics, muscle physiology, transcriptomics and ChIP-sequencing analyses, we have identified a signaling fingerprint linking the muscle cytoskeleton to dynamic changes in epigenetic markers on genes involved in muscle remodelling. We are now further exploring this link between mechanical stress associated with exercise intensity, and changes in gene transcription important for muscle plasticity, in both mice and humans.
The role of circadian rhythms in regulating muscle function
The circadian timing system controls physiology and metabolism through the coordinated interaction of a central pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus and peripheral clocks present in all tissues. The functional significance of circadian rhythms is to promote appropriate physiological adaptations in anticipation to the different phases of the day-night cycle. For example, we have recently shown that the intrinsic muscle clock controls muscle insulin sensitivity and glucose metabolism in order to prepare the tissue for the transition from the sleep/fasting phase to the wake/feeding phase, when glucose becomes the predominant fuel for skeletal muscle (Dyar et al 2014). Importantly, we also showed that muscle activity plays a key role in the regulation of some important genes involved in muscle plasticity (Dyar et al., 2015). Now, we are examining the importance of muscle circadian rhythms on force production.
- Pereira MG, Dyar KA, Nogara L, Solagna F, Marabita M, Baraldo M, Chemello F, Germinario E, Romanello V, Nolte H and Blaauw B. Comparative Analysis of Muscle Hypertrophy Models Reveals Divergent Gene Transcription Profiles and Points to Translational Regulation of Muscle Growth through Increased mTOR Signaling. Frontiers in Physiology, in press
- Marabita M, Baraldo M, Solagna F, Ceelen JJM, Sartori R, Nolte H, Nemazanyy I, Pyronnet S, Kruger M, Pende M, Blaauw B. S6K1 is required for increasing skeletal muscle force during hypertrophy, Cell Reports, 2016 Oct 4;17(2):501-513.
- Dyar KA, Ciciliot S, Malagoli Tagliazucchi G, Pallafacchina G, Tothova J, Argentini C, Agatea L, Abraham R, Ahdesmäki M, Forcato M, Bicciato S, Schiaffino S, Blaauw B. The calcineurin-NFAT pathway controls activity-dependent circadian gene expression in slow skeletal muscle. Molecular Metabolism, 2015 Sep 25;4(11):823-33
- Blaauw B, Schiaffino S, Reggiani C. Mechanisms modulating muscle phenotype. Compr Physiol. 2013 Oct 1;3(4):1645-87.
- Blaauw B*, Agatea L, Toniolo L, Canato M, Quarta M, Dyar KA, Danieli-Betto D, Betto R, Schiaffino S, Reggiani C. Eccentric contractions lead to myofibrillar dysfunction in muscular dystrophy. J Appl Physiol. 2010 Jan;108(1):105-11.
- Blaauw B*, Canato M, Agatea L, Toniolo L, Mammucari C, Masiero E, Abraham R, Sandri M, Schiaffino S, Reggiani C. Inducible activation of Akt increases skeletal muscle mass and force without satellite cell activation. FASEB J. 2009 Nov;23(11):3896-905.
- Blaauw B, Mammucari C, Toniolo L, Agatea L, Abraham R, Sandri M, Reggiani C, Schiaffino S. Akt activation prevents the force drop induced by eccentric contractions in dystrophin-deficient skeletal muscle. Hum Mol Genet. 2008 Dec 1;17(23):3686-96.
- Sartori R, Schirwis E, Blaauw B, Bortolanza S, Zhao J, Enzo E, Stantzou A, Mouisel E, Toniolo L, Ferry A, Stricker S, Goldberg AL, Dupont S, Piccolo S, Amthor H & Sandri M. BMP signaling controls muscle mass. Nat Genet. 2013 Nov;45(11):1309-18
- Masiero E, Agatea L, Mammucari C, Blaauw B, Loro E, Komatsu M, Metzger D, Reggiani C, Schiaffino S, Sandri M. Autophagy is required to maintain muscle mass. Cell Metab. 2009 Dec;10(6):507-15
- Milan G, Romanello V, Pescatore F, Armani A, Paik JH, Frasson L, Seydel A, Zhao J, Abraham R, Goldberg AL, Blaauw B, DePinho RA, Sandri M. Regulation of autophagy and the ubiquitin-proteasome system by the FoxO transcriptional network during muscle atrophy. Nat Commun. 2015 Apr 10;6:6670.
- PhD; Neurobiology, University of Padova, Italy (2008)
- Postdoc: Venetian Institute of Molecular Medicine (VIMM), Padova, Italy (2008 – 2011)
- Assistant Professor: Department of Biomedical Sciences, University of Padova, Italy (2011 – 2016)
- Group leader: Venetian Institute of Molecular Medicine (VIMM), Padova, Italy (since 2012)
- Associate Professor: Department of Biomedical Sciences, University of Padova, Italy (since 2016)
- 2014 – Young Italian Physiologist of the year