Generalmente il venerdì pomeriggio (15.00-18.00), stanza A1.40 Dipartimento di Biologia (Polo Scientifico di Sesto Fiorentino, Via Madonna del Piano 6).
Prego gli studenti di contattarmi per email (marco.linari@unifi.it) oppure per telefono (055 457 4754) per confermare giorno e orario.
Marco Linari
https://orcid.org/0000-0001-6512-4897
Dati da Scopus: lavori in extenso, 71; citazioni, 3150; h-index 32
Carriera accademica
- 1990: Laurea in Scienze Naturali
1995: Dottorato in FisiologiaCarriera accademica
1990 - 1994: Studente di dottorato, Dipartimento di Scienze Fisiologiche, Università di Firenze
1996 - 1997: Borsista Post-dottorato, Dipartimento di Scienze Fisiologiche, Università di Florence
1997 - 2001: Ricercatore, Dipartimento di Scienze Fisiologiche, Università di Firenze2001 - Professore Associato, Dipartimento di Biologia Evoluzionistica, Università di Firenze
2012 - Professore Ordinario, Dipartimento di Biologia, Università di Firenze
Altre esperienze
1993 - 1994: Research Fellow, Dept. of Physiology, University College, London, United Kingdom
1998 - 2003: Visiting scientist nel laboratorio del Prof. R.W. Woledge, Dept. of Physiology, University College, London, United Kingdom e Institute of Human Performance, London, United Kingdom
Borse di studio
1993 Fellowship della comunità europea (Human Capital and Mobility programme)
Appartenenza a Istituzioni e Società scientifiche
- Associate Member della Marie Curie Fellowship Association
- Biophysical Society (USA)
- Società Italiana di Fisiologia (SIF)
- Centro Studi Dinamiche Complesse (CSDC)
Attività Scientifica
La mia attività scientifica riguarda lo studio del meccanismo molecolare della contrazione muscolare e della sua regolazione: come l’energia liberata dall’idrolisi dell’ATP sul sito catalitico del motore miosinico attaccato al filamento di actina è trasformata in forza e accorciamento a livello del sarcomero e quali sono i meccanismi che permettono l'attivazione della contrazione. Questi obiettivi sono perseguiti attraverso un approccio integrato che prevede la combinazione di tecniche di meccanica, biochimica, calorimetria e diffrazione a raggi X con luce di sincrotrone su preparati isolati da muscolo scheletrico (muscolo intero e singole fibre) e cardiaco (muscolo papillare e trabecole).
Pubblicazioni
Riviste peer-reviewed: 71 (tra cui 5 in Nature, 1 in Cell, 1 in Nature Communications, 6 in PNAS, 2 in Faseb Journal, 1 in JCSM, 1 in Communication Biology, 19 in The Journal of Physiology)
Contributo a libro: 8
Seminari su invito: 20
Abstracts a conferenze: 151
Organizzazione congressi/simposi
50th European Muscle Conference (2023, Florence, Italy)
69th Italian Physiological Society Congress (2018, Firenze, Italy)
Symposium “Structure-function relation in the myosin II motor” - Europhysiology Meeting (2018, London, United Kingdom)
9th Young Reseachers Meeting (2015, Firenze, Italy)
33rd European Muscle Conference (2004, Isola d’Elba, Livorno, Italy)
9th Congress of the Italian Synchrotron Radiation Society (2001, Firenze, Italy)
Incarichi di insegnamento/istituzionali
Dal 1999, insegnamento di Fisiologia generale, Fisiologia integrativa e Neurobiologia (Università di Firenze) Tutor di 5 studenti di dottorato
- 2011-2015: presidente del Corso di Laurea Unico in Scienze Biologiche e della laurea Magistrale in Biologia (Università di Firenze)
- 2015-2016: membro del Senato Accademico (Università di Firenze)
- 2017-2020: membro del Consiglio di Amministrazione (Università di Firenze)
Finanziamenti negli ultimi 5 anni
- Ministero dell’Università e della Ricerca (PRIN-PNRR 2022)
2023-2025 “Regulation of striated muscle: a research bridging single molecule to organ"
Role: Coordinator
- AFM Telethon France
2023-2024 "Titinopathies – disease models for translational therapeutics"
Role: Participant
Coordinator, Udd Bjarne
- Enlarged Partnership 8 (MUR – NRRP, Next Generation EU)
2023-2026 “Ageing well in an ageing society - Age-It
”Role: Participant (WP6, Therapeutic targets of the Spoke 2, Improving the understanding of the biology of ageing)
Coordinator, Daniele Vignoli
- Ministero dell’Università e della Ricerca (PRIN)
2021-2024 “The structural and functional role of the A-kinase anchoring protein myospryn in striated muscle”
- European Joint Programme on Rare Diseases (EJP RD), EU grant Udd Bjarne (Corrdinator)
2020-2023 “Improved diagnostic output in large sarcomeric genes” Miglioramento della pipeline diagnostica per le patologie rare dei muscoli scheletrici causate da mutazioni nei geni di grandi dimensioni (titina e nebulina).
Role: Local PI
Lavori in extenso negli ultimi 5 anni
1) M. Caremani, M. Marcello, I. Morotti, I. Pertici, C. Squarci, M. Reconditi, P. Bianco, G. Piazzesi, V. Lombardi, M. Linari. The force of the myosin motor sets cooperativity in thin filament activation of skeletal muscles. Commun Biol, 5:1266, 2022.
2) M. Caremani, L. Fusi, M. Linari, M. Reconditi, G. Piazzesi, T.C. Irving, T. Narayanan, M. Irving, V. Lombardi, E. Brunello. Dependence of thick filament structure in relaxed mammalian skeletal muscle on temperature and inter-filament spacing. J Gen Physiol, 153:e202012713, 2021.
3) S. Governali, M Caremani, C. Gallart, I. Pertici, G. Stienen, G. Piazzesi, C. Ottenheijm, V. Lombardi, M. Linari. Orthophosphate increases the efficiency of slow muscle-myosin isoform in the presence of omecamtiv mecarbil. Nature Communications, 11:3405, 2020.
4) M. Linari, G. Piazzesi, I. Pertici, J.A. Dantzig, Y.E. Goldman, V. Lombardi. Straightening out the elasticity of myosin cross-bridges. Biophys J 118:994-1002, 2020.
5) M.C. Filomena, D.L. Yamamoto, M. Caremani, V.K. Kadarla, G. Mastrototaro, S. Serio, A. Vydyanath, M. Mutarelli, A. Garofalo, I. Pertici, R. Knöll, V. Nigro, P.K. Luther, R.L. Lieber, M.R. Beck, M. Linari, and M.L. Bang. Myopalladin promotes muscle growth through modulation of the serum response factor pathway. Journal of Cachexia, Sarcopenia and Muscle 11:169-194, 2020.
6) M. Caremani, E. Brunello, M. Linari, L. Fusi, T. Irving, D. Gore, G. Piazzesi, M. Irving, V. Lombardi, M. Reconditi. Low temperature traps myosin motors of mammalian muscle in a refractory state that prevents activation. J Gen Physiol, 151:1272-1286, 2019.
7) M. Reconditi, L. Fusi, M. Caremani, E. Brunello, M. Linari, G. Piazzesi, V. Lombardi, M. Irving. Thick filament length changes in muscle have both elastic and structural components. Biophys J, 116:983-984, 2019.
8) M. Caremani, F. Pinzauti, J.D. Powers, S. Governali, T. Narayanan, G.J.M. Stienen, M. Reconditi, M. Linari, V. Lombardi, G. Piazzesi. Inotropic interventions do not change the resting state of myosin motors during cardiac diastole. J Gen Physiol, 151:53, 2019.
9) G. Piazzesi, M. Caremani, M. Linari, M. Reconditi, V. Lombardi. Thick filament mechano-sensing in skeletal and cardiac muscles: a common mechanism able to adapt the energetic cost of the contraction to the task. Frontiers in Physiology, 9:736, 2018.
10) F. Pinzauti, I. Pertici, M. Reconditi, T. Narayanan, G.J.M. Stienen, G. Piazzesi, V. Lombardi, M. Linari, M. Caremani. The force and stiffness of myosin motors in the isometric twitch of a cardiac trabecula and the effect of the extracellular Calcium concentration. J Physiol, 596:2581-2596, 2018.11) M. Reconditi, M. Caremani, F. Pinzauti, J. Powers, T Narayanan, G.J.M. Stienen, M. Linari, V. Lombardi, G. Piazzesi. Myosin filament activation in the heart is tuned to the mechanical task. PNAS, 114:3240-3245, 2017.
Legenda
Data from Scopus:
- full refereed papers, 77
- number of citations, 3457
- h-index 34
Education and training
1990: Laurea cum laude in Natural Sciences, University of Florence.
1993-1994: Visiting scientist in Prof RC Woledge laboratory, Dept of Physiology, UCL, London.
1995: PhD in Physiology, University of Florence.
1995-1997: Postdoc, Dept of Physiological Sciences, University of Florence.
1998-2009: Visiting scientist (1-2 months per year) in Prof RC Woledge laboratory at the Royal National Orthopaedic Hospital, London, UK and Imperial College London, London, UK. Employment
1993-1994: Research Assistant in the Dept of Physiology, UCL, London.
1997-2001: Researcher, Dept of Physiological Sciences, University of Florence.
2001-2012: Associate Professor of Physiology, Dept of Physiological Sciences and Dept of Biology (since 2004), University of Florence.
2012-present: Professor of Physiology, Dept of Biology, University of Florence.
Research activity
My research activity concerns the study of the molecular mechanisms of muscle contraction, regulation and modulation of contraction in relation to sarcomeric and cytoskeleton proteins in wild type and KO vertebrate models. These goals are pursued through an integrated approach that involves combining mechanical, biochemical, calorimetry and X-ray diffraction techniques in skeletal muscle fibres/muscles and cardiac trabeculae. Using these approaches the mechano-chemistry and structural dynamics of the muscle myosin in situ, a new regulatory system based on myosin filament mechano-sensing and the functional role of nebulin and myopalladin in relation to muscle contraction have been defined.
Scientific achievements
1. Mechanical, kinetic and energetic properties of the molecular motor studied in skeletal muscle fibres. Contraction of striated muscle consists in generation of force and shortening in each sarcomere, the structural unit of the muscle, by two bipolar arrays of myosin motors emerging from the thick filament and pulling the overlapping actin-containing thin filaments toward the centre of the sarcomere during cyclical ATP-driven working strokes. Exploiting a fast opto-mechanical setup first devised by Sir Andrew Huxley, the action of the motors working in parallel in each half-sarcomere can be synchronised determining the elastic and working stroke properties of the myosin motors in situ (Lombardi et al Nature 355:638, 1992; Linari et al Biophys J 96:583, 2009; Park-Holohan et al J Physiol 590:1973, 2012; Piazzesi et al ABB, 552:108, 2014). Combining fast mechanics with microcalorimetry the energetics of shortening and lengthening contraction have been determined in single skeletal muscle cells (Linari and Woledge J Physiol 487:699, 1995; Linari et al J Physiol 548:461, 2003).
2. Chemo-mechanical coupling investigated at sarcomere level in demembranated fibres of skeletal muscle. In demembranated fibres the mechanical properties can be correlated to the biochemical state of the myosin motor. By synchronising the action of the myosin motors with force steps in the presence of different concentration of Ca2+ and inorganic phosphate (Pi) it has been found that, in contrast to the assumption from crystallographic models, the release of ATP hydrolysis products (Pi and ADP) from the catalytic site of a myosin motor and the execution of the working stroke are not tightly coupled (Linari et al Proc R Soc B 277:19, 2010, Caremani et al J Physiol 591:5187, 2013; Caremani et al J Physiol 593:3313, 2015).
3. Structural dynamics of the molecular motor studied by X-ray diffraction and second harmonic generation microscopy. X-ray diffraction allows recording time resolved structural changes in the myosin motor in situ. The high collimation of the beam of 3rd generation synchrotrons made it possible to record the fine structure of the myosin-based reflections due to X-ray interference between the two arrays of motors in the thick filament (Linari et al PNAS 97:7226, 2000). In this way we measured the size of the working stroke in situ (Reconditi et al Nature 428: 578, 2004) and defined the molecular basis of the efficiency of skeletal muscle during steady power production (Piazzesi et al Cell 131:784, 2007). Then we showed the structural changes in the myosin motors during isometric force development (Reconditi et al PNAS 108:7236, 2011), as well as the contribution of the myofilaments to the half-sarcomere compliance (Brunello et al J Physiol 592:3881, 2014). Using second harmonic generation microscopy in single intact frog fibres we found that 30% of the available myosin motors are attached during an isometric contraction in vivo (Nucciotti et al PNAS 107:7763, 2010).
4. Regulation of muscle contraction in skeletal and cardiac muscles. In resting muscle the myosin motors are packed into helical tracks on the surface of the thick filaments (OFF state), making them unavailable for actin binding and ATP hydrolysis. This raises the question of how the myosin motor can sense the state of the thin filament during contraction. Combining sarcomere level mechanics and X-ray interference a novel thick filament based regulation of muscle contraction has been discovered first in skeletal muscle (Linari et al Nature 582:276, 2015) and then in cardiac muscle (Reconditi et al PNAS 114:3240, 2017). This regulation is based on thick filament mechano-sensing, which adapts to the external load the fraction of motors recruited from the OFF state. In the heart, these results indicate that, independent of the end-diastolic volume, the energetic cost of the heartbeat is tuned to the load determined by the arterial pressure. The interdependency of the thin and thick filament regulatory mechanisms in intact trabeculae was then tested by recording the X-ray diffraction signals that mark the state of the thick filament during inotropic interventions (increase in sarcomere length, and addition of the β-adrenergic effector isoprenaline), which potentiate the twitch force by twofold. During diastole, none of the signals related to the resting state of the myosin motors were affected by these interventions, indicating that recruitment of myosin motors from their resting state occurs downstream from thin filament activation (Caremani et al J Gen Physiol 151:53, 2019). A deterioration of the thick and thin filament regulation due to mutations in sarcomeric proteins causes either hypertrophic (HCM) or dilated (DCM) cardiomyopathy. Among the small molecule effectors under study as new therapeutic tools to cure DCM, omecamtiv mecarbil (OM) is in phase 3 clinical trial as a cardiac myosin activator. In Ca2+-activated demembranated fibres from rabbit soleus (which has the same myosin isoform as the mammalian ventricle), we found that OM, beyond the known increase in Ca2+-sensitivity of filament activation, in the presence of physiological concentration of phosphate is responsible for a reduction of the tension cost (Governali et al Nat Commun 11:3405, 2020).
5. Modulation of contraction by sarcomeric and cytoplasmic proteins. In collaboration with Marie-Louise Bang (Istituto di Ricerca Genetica e Biomedica, CNR Milano), the role of nebulin (an actin associated protein) and myopalladin (a striated muscle-specific protein located in the Z-line and I-band of the sarcomere) has been studied by comparing the performance of demembranated fibre/intact muscle from control and KO mice revealing that nebulin has a fundamental role in modulating muscle contraction (Bang et al Faseb J 23:4117, 2009) while myopalladin promotes skeletal muscle growth (Filomena et al JCSM 11:169, 2020). The molecular basis of the contribution of titin in the passive force response following a stretch has been studied integrating single fibre mechanics and single molecule mechanics in collaboration with Miklos Kellermayer (Semmelweis University, Budapest Hungary). The results show that the PEVK domain of the titin molecule contributes to the force response induced by the sarcomere lengthening (Martonfalvi et al JCS 127:858, 2014).
Publications and talks at a glance (data from Scopus)
- full refereed papers, 71 (among which 1 in Cell, 5 in Nature, 1 in Nature Commun, 6 in PNAS, 2 in Faseb Journal, 18 in The Journal of Physiology)
- invited talks in conferences: 20
- abstracts in conference proceedings: 151
Grants (last 5 years)
2023-2026“Ageing well in an ageing society - Age-It”
Role: Participant (WP6, Therapeutic targets of the Spoke 2, Improving the understanding of the biology of ageing)
- Ministero dell’Università e della Ricerca (PRIN)(2022-2024)
“The structural and functional role of the A-kinase anchoring protein myospryn in striated muscle”
- European Joint Programme on Rare Diseases (EJP RD), EU grant (2020-2023)
“Improved diagnostic output in large sarcomeric genes”
Role: Italian partner
Invited speaker at international conferences
- 2021: Ruzzier Lecture, 71° Congresso della Società Italiana di Fisiologia (7-9 Settembre, Milano, Italy)
- 2020: HiLIFE webinar / Biomedicum Helsinki seminar (9 November, Helsinki, Finland)
- 2018: IIT Genoa (17 December, Italy)
- 2018: 12th Annual Meeting of Young Researchers (3-5 May, Anacapri, Naples, Italy)
- 2017: 14th IIM Meeting (12-15 October, Assisi, Italy)
- 2016: Myosin & Muscle, and other Motors (12-18 Mach, Alpbach, Austria)
- 2015: 44th European Muscle Conference (21-25 September, Warsaw, Poland)
- 2012: 8th European Solid Mechanics Conference (9-13 July, Graz, Austria)
- 2005: Gordon Research Conference (Colby Sawyer College, New London, New Hampshire, USA)
- 2001: 30th European Muscle Conference (9-12 September, Pavia, Italy)
- 2000: 3rd Conference on Molecular Recognition (Pécs, Ungheria)
- 1999: Gordon Research Conference (Colby Sawyer College, New London, New Hampshire, USA)
- 1998: London Muscle Series, NUMR (Mill Hill, London, UK)
- 1998: 9th Alpbach Muscle Workshop (Alpbach, Austria)- 1997: EC Network Meeting (Gunzburg, Germany)
- 1996: EC Network Meeting (Zell am See, Austria)
- 1995: 8th Alpbach Workshop (Alpbach, Austria)- 1992: EEC Muscle Groups Meeting (San Miniato, Pisa, Italy)
Lecture at international PhD school
- 2018: 12th Annual Meeting of Young Researchers in Physiology (3-5 May, Anacapri, Naples, Italy)
- 2018: Muscle Biophysics Summer School (28-30 August, Budapest, Hungary)
Several research presentations at national (Italian Physiological Society) and international meetings (Biophysical Society, USA; Physiological Society, UK). Seminars in research institutes in Italy and abroad (National Institute for Medical Research, London, UK; University College London, UK; Imperial College London, UK).
Organization of Conferences/Symposium at conferences
- 2024: Co-chair of the session “Muscle Mechanics and Contractility” at the 51st European Muscle Conference (22-24 September, Ljubljana, Slovenia)
- 2023: Organising Committee of the 50th European Muscle Conference (4-8 September, Florence, Italy)
- 2020: Member of the Scientific Committee for the Virtual Physiological Human meeting (VPH2020, Paris, France, 26-28 August 2020)
- 2018: Organiser of the symposium “Structure-function relation in the myosin II motor”, Europhysiology Meeting (14-16 September, London, United Kingdom)
- 2018: Chair of the session “Striated Muscle Mechanics” at the 47th European Muscle Conference (30 August – 3 September, Budapest, Hungary)
- 2015: Organising Committee of the 9th Young Reseachers Meeting in Physiology (14-16 May, Firenze, Italy)
- 2004: Organising Committee of the XXXIII European Muscle Conference (19-23 September, Isola d’Elba, Livorno, Italy)
- 2001: Organising Committee of the IX Congress of the Italian Synchrotron Radiation Society (5-7 July, Firenze, Italy)Teaching and Institutional roles
Teaching activity and institutional position
- 1999-actual: lecture/professor of General Physiology, Integrative Physiology and Neurobiology (degree courses in Biology and Optics and Optometry, master degree course in Biology, University of Florence).
- Tutor of 9 undergraduate students (degree and master degree in Biology and Natural Sciences); tutor of 5 PhD student (University of Florence and Siena).
- 2011-2015: chair of the degree course and master degree course in Biology, University of Florence. - 2015-2016: member of the Academic Senate of the University of Florence (scientific area).
- 2017-2020: member of the Administration Board of the University of Florence.
Papers in extenso in the last 5 years
1) M. Marcello, V. Cetrangolo, I. Morotti, C. Squarci, M. Caremani, M. Reconditi, M. Savarese, P. Bianco, G. Piazzesi, V. Lombardi, B. Udd, I. Conte, V. Nigro, M. Linari. Sarcomere level mechanics of the fast skeletal muscle of the new myopathy model medaka fish. Am J Physiol 326: C632-C644, 2024.
2) M. Caremani, M. Marcello, I. Morotti, I. Pertici, C. Squarci, M. Reconditi, P. Bianco, G. Piazzesi, V. Lombardi, M. Linari. The force of the myosin motor sets cooperativity in thin filament activation of skeletal muscles. Commun Biol, 5:1266, 2022.
3) M. Caremani, L. Fusi, M. Linari, M. Reconditi, G. Piazzesi, T.C. Irving, T. Narayanan, M. Irving, V. Lombardi, E. Brunello. Dependence of thick filament structure in relaxed mammalian skeletal muscle on temperature and inter-filament spacing. J Gen Physiol, 153:e202012713, 2021.
4) S. Governali, M Caremani, C. Gallart, I. Pertici, G. Stienen, G. Piazzesi, C. Ottenheijm, V. Lombardi, M. Linari. Orthophosphate increases the efficiency of slow muscle-myosin isoform in the presence of omecamtiv mecarbil. Nature Communications, 11:3405, 2020.
5) M. Linari, G. Piazzesi, I. Pertici, J.A. Dantzig, Y.E. Goldman, V. Lombardi. Straightening out the elasticity of myosin cross-bridges. Biophys J 118:994-1002, 2020.
6) M.C. Filomena, D.L. Yamamoto, M. Caremani, V.K. Kadarla, G. Mastrototaro, S. Serio, A. Vydyanath, M. Mutarelli, A. Garofalo, I. Pertici, R. Knöll, V. Nigro, P.K. Luther, R.L. Lieber, M.R. Beck, M. Linari, and M.L. Bang. Myopalladin promotes muscle growth through modulation of the serum response factor pathway. Journal of Cachexia, Sarcopenia and Muscle 11:169-194, 2020.
7) M. Caremani, E. Brunello, M. Linari, L. Fusi, T. Irving, D. Gore, G. Piazzesi, M. Irving, V. Lombardi, M. Reconditi. Low temperature traps myosin motors of mammalian muscle in a refractory state that prevents activation. J Gen Physiol, 151:1272-1286, 2019.
8) M. Reconditi, L. Fusi, M. Caremani, E. Brunello, M. Linari, G. Piazzesi, V. Lombardi, M. Irving. Thick filament length changes in muscle have both elastic and structural components. Biophys J, 116:983-984, 2019.
9) M. Caremani, F. Pinzauti, J.D. Powers, S. Governali, T. Narayanan, G.J.M. Stienen, M. Reconditi, M. Linari, V. Lombardi, G. Piazzesi. Inotropic interventions do not change the resting state of myosin motors during cardiac diastole. J Gen Physiol, 151:53, 2019.
10) G. Piazzesi, M. Caremani, M. Linari, M. Reconditi, V. Lombardi. Thick filament mechano-sensing in skeletal and cardiac muscles: a common mechanism able to adapt the energetic cost of the contraction to the task. Frontiers in Physiology, 9:736, 2018.
11) F. Pinzauti, I. Pertici, M. Reconditi, T. Narayanan, G.J.M. Stienen, G. Piazzesi, V. Lombardi, M. Linari, M. Caremani. The force and stiffness of myosin motors in the isometric twitch of a cardiac trabecula and the effect of the extracellular Calcium concentration. J Physiol, 596:2581-2596, 2018.
