Bert Blaauw

• 

  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.

  Background

  Research

  Group Members

  Key Publications

  In the last 20 years the intra-and extracellular pathways regulating adult skeletal muscle mass are starting to be unravelled. Despite a significant increase in the knowledge regarding intracellular mediators of muscle growth, currently no drugs exist to counteract muscle wasting. More importantly, in numerous pathologies the drop in muscle force production or its resistance to fatigue is more pronounced and precedes the loss in muscle mass. Despite its importance, the signaling pathways stimulating muscle function are only now starting to be unravelled. The Blaauw lab has increased the understanding of how the Akt-mTOR pathway, a critical regulator of adult skeletal muscle mass, can also modulate muscle contractile properties. We are currently trying to understand how this pathway can regulate muscle function and how it is affecting muscle remodelling after exercise. Furthermore, we are investigating how its dysregulation in various diseases, like cancer and aging, affects muscle performance.

  Ongoing activities

  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.

  

  Leonardo Nogara

  Post-Doc

  leonardo.nogara@unipd.it

  

  Martina Baraldo

  PhD student

  martina.baraldo@studenti.unipd.it

  

  Elena Germinario

  Technician

  elena.germinario@unipd.it

  

  Alessia Geremia

  PhD student

  geremia.alessia@gmail.com

  

  Georgia Dumitras

  PhD Student

  dmtgeorgia@gmail.com

  

  Stefano Ciciliot

  Post-Doc

  stefano.ciciliot@unipd.it

  1. Blaauw B. Activity-dependent increases of protein synthesis in skeletal muscle: Sensing the energy levels? J Physiol. 2020 May 16.
  2. Solagna F, Nogara L, Dyar KA, Greulich F, Mir AA, Türk C, Bock T, Geremia A, Baraldo M, Sartori R, Farup J, Uhlenhaut H, Vissing K, Kruger M, Blaauw B. Exercise-dependent increases in protein synthesis are accompanied by chromatin modifications and increased MRTF-SRF signaling. Acta Physiol (Oxf). 2020 May 14
  3. Kallabis S, Abraham L, Müller S, Dzialas V, Türk C, Wiederstein JL, Bock T, Nolte H, Nogara L, Blaauw B, Braun T, Krüger M. High-throughput proteomics fiber typing (ProFiT) for comprehensive characterization of single skeletal muscle fibers. Skelet Muscle. 2020 Mar 23;10(1):7.
  4. de Winter JM, Molenaar JP, Yuen M, van der Pijl R, Shen S, Conijn S, van de Locht M, Willigenburg M, Bogaards SJ, van Kleef ES, Lassche S, Persson M, Rassier DE, Sztal TE, Ruparelia AA, Oorschot V, Ramm G, Hall TE, Xiong Z, Johnson CN, Li F, Kiss B, Lozano-Vidal N, Boon RA, Marabita M, Nogara L, Blaauw B, Rodenburg RJ, Küsters B, Doorduin J, Beggs AH, Granzier H, Campbell K, Ma W, Irving T, Malfatti E, Romero NB, Bryson-Richardson RJ, van Engelen BG, Voermans NC, Ottenheijm CA. KBTBD13 is an actin-binding protein that modulates muscle kinetics. J Clin Invest. 2020 Feb
  5. Baraldo M, Geremia A, Pirazzini M, Nogara L, Solagna F, Türk C, Nolte H, Romanello V, Megighian A, Boncompagni S, Kruger M, Sandri M, Blaauw B. Skeletal muscle mTORC1 regulates neuromuscular junction stability. J Cachexia Sarcopenia Muscle. 2020 Feb;11(1):208-225
  6. D'Hulst G, Soro-Arnaiz I, Masschelein E, Veys K, Fitzgerald G, Smeuninx B, Kim S, Deldicque L, Blaauw B, Carmeliet P, Breen L, Koivunen P, Zhao SM, De Bock K. PHD1 controls muscle mTORC1 in a hydroxylation-independent manner by stabilizing leucyl tRNA synthetase.  Nat Commun. 2020 Jan 10;11(1):174.
  7. Pozzer D, Invenizzi RW, Blaauw B, Cantoni O, Zito E. Ascorbic Acid Route to the Endoplasmic Reticulum: Function and Role in Disease. Antioxid Redox Signal. 2020 Jan 22
  8. Romanello V, Scalabrin M, Albiero M, Blaauw B, Scorrano L, Sandri M. Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal Muscles. Cells. 2019 Jun 15;8(6):597.
  9. Favaro G, Romanello V, Varanita T, Andrea Desbats M, Morbidoni V, Tezze C, Albiero M, Canato M, Gherardi G, De Stefani D, Mammucari C, Blaauw B, Boncompagni S, Protasi F, Reggiani C, Scorrano L, Salviati L, Sandri M. DRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass. Nat Commun. 2019 Jun 12;10(1):2576.
  10. Varone E, Pozzer D, Di Modica S, Chernorudskiy A, Nogara L, Baraldo M, Cinquanta M, Fumagalli S, Villar-Quiles RN, De Simoni MG, Blaauw B, Ferreiro A, Zito E. SELENON (SEPN1) protects skeletal muscle from saturated fatty acid-induced ER stress and insulin resistance. Redox Biol. 2019 Jun;24:101176
  11. Oost LJ, Kustermann M, Armani A, Blaauw B, Romanello V. Fibroblast growth factor 21 controls mitophagy and muscle mass. Sarcopenia Muscle. 2019 Jun;10(3):630-642.
  12. Galazzo L, Nogara L, LoVerso F, Polimeno A, Blaauw B, Sandri M, Reggiani C, Carbonera D.
  13. Am J Changes in the fraction of strongly attached cross bridges in mouse atrophic and hypertrophic muscles as revealed by continuous wave electron paramagnetic resonance.Physiol Cell Physiol. 2019 May
  14. Varone E, Pozzer D, Di Modica S, Chernorudskiy A, Nogara L, Baraldo M, Cinquanta M, Fumagalli S, Villar-Quiles RN, De Simoni MG, Blaauw B, Ferreiro A, Zito E.
  15. SELENON (SEPN1) protects skeletal muscle from saturated fatty acid-induced ER stress and insulin resistance. Redox Biol. 2019 Mar 23
  16. Oost LJ, Kustermann M, Armani A, Blaauw B, Romanello V.
  17. J Cachexia Fibroblast growth factor 21 controls mitophagy and muscle mass.Sarcopenia Muscle. 2019 Mar
  18. Pozzer D, Varone E, Chernorudskiy A, Schiarea S, Missiroli S, Giorgi C, Pinton P, Canato M, Germinario E, Nogara L, Blaauw B, Zito E. A maladaptive ER stress response triggers dysfunction in highly active muscles of mice with SELENON loss. Redox Biology Jan 2019
  19. Rashid T, Nemazanyy I, Paolini C, Tatsuta T, Crespin P, Brodesser S, Benit P, Rustin P, Baraibar MA, Agbulut O, Olivier A, Protasi F, Langer T, Chrast R, de Lonlay P, de Foucauld H, Blaauw B, Pende M.  Lipin1 deficiency causes sarcoplasmic reticulum stress and chaperone-responsive myopathy. EMBO J Jan 2019.
  20. Lang F, Khaghani S, Türk C, Wiederstein JL, Hölper S, Piller T, Nogara L, Blaauw B, Günther S, Müller S, Braun T, Krüger M. Single Muscle Fiber Proteomics Reveals Distinct Protein Changes in Slow and Fast Fibers during Muscle Atrophy. J Proteome Res Oct 2018 5;17(10):3333-3347
  21. Ferlin A, De Toni L, Agoulnik AI, Lunardon G, Armani A, Bortolanza S, Blaauw B, Sandri M, Foresta C. Protective Role of Testicular Hormone INSL3 From Atrophy and Weakness in Skeletal Muscle. Front Endocrinol (Lausanne) 2018 Sep 28;9:562.
  22. Gherardi G, Nogara L, Ciciliot S, Fadini GP, Blaauw B, Braghetta P, Bonaldo P, De Stefani D, Rizzuto R, Mammucari C. Loss of mitochondrial calcium uniporter rewires skeletal muscle metabolism and substrate preference. Cell Death Differ Sep 2018. 19
  23. Vitiello L, Marabita M, Sorato E, Nogara L, Forestan G, Mouly V, Salviati L, Acosta M, Blaauw B, Canton M. Drug Repurposing for Duchenne Muscular Dystrophy: The Monoamine Oxidase B Inhibitor Safinamide Ameliorates the Pathological Phenotype in mdx Mice and in Myogenic Cultures From DMD Patients. Front Physiol Aug 2018 14;9:1087
  24. Dyar KA, Hubert MJ, Mir AA, Ciciliot S, Lutter D, Greulich F, Quagliarini F, Kleinert M, Fischer K, Eichmann TO, Wright LE, Peña Paz MI, Casarin A, Pertegato V, Romanello V, Albiero M, Mazzucco S, Rizzuto R, Salviati L, Biolo G, Blaauw B,  Schiaffino S, Uhlenhaut NH. Transcriptional programming of lipid and amino acid metabolism by the skeletal muscle circadian clock. PLoS Biol Aug 2018 10;16(8):
  25. Urciuolo A, Urbani L, Perin S, Maghsoudlou P, Scottoni F, Gjinovci A, Loukogeorgakis S, Tyraskis A, Torelli S, Germinario E, Alvarez Fallas ME, Julia-Vilella C, Eaton S, Blaauw B, De Coppi P. (2018). Acellular skeletal muscles rescue volumetric muscle loss defects. Scientific Reports May 2018 30;8(1):8398:
  26. Wiederstein J, Nolte H, Günther S, Piller T, Baraldo M, Kostin S, Bloch W, Sandri M, Blaauw B, Braun T, Hölper S and Krüger M. Skeletal muscle-specific methyltransferase METTL21C trimethylates p97 and regulate autophagy-associated protein breakdown. Cell Reports 2018 May
  27. 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 Dec 2017 4;8:968
  28. 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
  29. 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
  30. 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.
  31. Blaauw B, Schiaffino S, Reggiani C. Mechanisms modulating muscle phenotype. Compr Physiol. 2013 Oct 1;3(4):1645-87.
  32. 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
  33. 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.
  34. 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.
  35. 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
  36. 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.

  

  BERT BLAAUW

  • 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)

  Selected Awards

  • 2014 – Young Italian Physiologist of the year

  Current funding

  • Fondazione AIRC
  • AFM Telethon