Mechanobiology

Since the 19th century we’ve known that high blood pressure is linked to pathological cardiac remodeling. Myocytes respond to altered loads by growing in thickness or length, and if unchecked this leads to dysfunction and heart failure.  Yet after a century of research, we know very little about how a myocyte senses a change in force and transduces that to a cellular response.

A flurry of elegant studies – mainly conducted in non-muscle cells – shows that force can be transmitted through the cytoskeleton to affect nuclear remodeling, chromatin architecture and gene expression. But this field of nuclear mechanobiology is young, and little has been done in the myocyte, despite its fundamental importance and unique mechanical niche.

We seek to define 1) the cytoskeletal conduits for force transmission to the nucleus during the contractile cycle, 2) how force regulates chromatin architecture and gene expression in beating cardiomyocytes, 3) how genetic variants that compromise nuclear mechanotransduction lead to disease (i.e. laminopathies).

To accomplish these aims we use custom engineered systems to precisely control stress and strain on myocardial cells and tissue.  We combine this with super-resolution microscopy to reveal sub-cellular responses to changing mechanical loads.  We marry these single cell biophysical approaches with “omic” level assays chromatin architecture and clinical data to integrate our understanding. We rely on animal models for genetic control, but devote equal effort to functional studies in human myocytes and engineered human myocardium to ensure relevance and foster translation.

Our lab catalyzes a unique interface between the Penn Cardiovascular Institute (CVI), Penn Muscle Institute (PMI), and the Center for Engineering Mechanobiology (CEMB).  We fuse this expertise to tackle clinically vital applications with single molecule precision, with the goal of transformative insight into how the heart responds to force.

Related Publications

Desmin intermediate filaments and tubulin detyrosination stabilize growing microtubules in the cardiomyocyte.

Desmin intermediate filaments and tubulin detyrosination stabilize growing microtubules in the cardiomyocyte.

Salomon AK, Phyo SA, Okami N, Heffler J, Robison P, Bogush AI, Prosser BL.

Basic Res Cardiol. 2022 Nov 3;117(1):53. doi: 10.1007/s00395-022-00962-3. PMID: 36326891
Mechanobiology

Extracellular stiffness induces contractile dysfunction in adult cardiomyocytes via cell-autonomous and microtubule-dependent mechanisms.

Extracellular stiffness induces contractile dysfunction in adult cardiomyocytes via cell-autonomous and microtubule-dependent mechanisms.

Vite A, Caporizzo MA, Corbin EA, Brandimarto J, McAfee Q, Livingston CE, Prosser BL, Margulies KB.

Basic Res Cardiol. 2022 Aug 25;117(1):41. doi: 10.1007/s00395-022-00952-5. PMID: 36006489
Heart Failure Mechanobiology

The microtubule cytoskeleton in cardiac mechanics and heart failure.

The microtubule cytoskeleton in cardiac mechanics and heart failure.

Caporizzo MA, Prosser BL.

Nat Rev Cardiol. 2022 Jun;19(6):364-378. doi: 10.1038/s41569-022-00692-y. Epub 2022 Apr 19. PMID: 35440741
Heart Failure Mechanobiology

Cardiomyocyte Microtubules: Control of Mechanics, Transport, and Remodeling.

Cardiomyocyte Microtubules: Control of Mechanics, Transport, and Remodeling. 

Uchida K, Scarborough EA, Prosser BL.

Annu Rev Physiol. 2022 Feb 10;84:257-283. doi: 10.1146/annurev-physiol-062421-040656. Epub 2021 Oct 6. PMID: 34614374
Heart Failure RNA Biology Mechanobiology

Need for Speed: The Importance of Physiological Strain Rates in Determining Myocardial Stiffness. 

Need for Speed: The Importance of Physiological Strain Rates in Determining Myocardial Stiffness. 

Caporizzo MA, Prosser BL.

Front Physiol. 2021 Jul 30;12:696694. doi: 10.3389/fphys.2021.696694. eCollection 2021. PMID: 34393820
Heart Failure Mechanobiology

X-ROS Signaling Depends on Length-Dependent Calcium Buffering by Troponin. 

X-ROS Signaling Depends on Length-Dependent Calcium Buffering by Troponin. 

Limbu S, Prosser BL, Lederer WJ, Ward CW, Jafri MS.

Cells. 2021 May 13;10(5):1189. doi: 10.3390/cells10051189. PMID: 34068012
Mechanobiology

Cochlear supporting cells require GAS2 for cytoskeletal architecture and hearing. 

Cochlear supporting cells require GAS2 for cytoskeletal architecture and hearing. 

Chen T, Rohacek AM, Caporizzo M, Nankali A, Smits JJ, Oostrik J, Lanting CP, Kücük E, Gilissen C, van de Kamp JM, Pennings RJE, Rakowiecki SM, Kaestner KH, Ohlemiller KK, Oghalai JS, Kremer H, Prosser BL, Epstein DJ.

Dev Cell. 2021 May 17;56(10):1526-1540.e7. doi: 10.1016/j.devcel.2021.04.017. Epub 2021 May 7. PMID: 33964205
Mechanobiology

Microtubules orchestrate local translation to enable cardiac growth. 

Microtubules orchestrate local translation to enable cardiac growth. 

Scarborough EA, Uchida K, Vogel M, Erlitzki N, Iyer M, Phyo SA, Bogush A, Kehat I, Prosser BL.

Nat Commun. 2021 Mar 11;12(1):1547. doi: 10.1038/s41467-021-21685-4.

PMID: 33707436

RNA Biology Mechanobiology

Pathogenic LMNA variants disrupt cardiac lamina-chromatin interactions and de-repress alternative fate genes. 

Pathogenic LMNA variants disrupt cardiac lamina-chromatin interactions and de-repress alternative fate genes. 

Shah PP, Lv W, Rhoades JH, Poleshko A, Abbey D, Caporizzo MA, Linares-Saldana R, Heffler JG, Sayed N, Thomas D, Wang Q, Stanton LJ, Bedi K, Morley MP, Cappola TP, Owens AT, Margulies KB, Frank DB, Wu JC, Rader DJ, Yang W, Prosser BL, Musunuru K, Jain R.

Cell Stem Cell. 2021 May 6;28(5):938-954.e9. doi: 10.1016/j.stem.2020.12.016. Epub 2021 Feb 1. PMID: 33529599
Mechanobiology

Tubulin Detyrosination: An Emerging Therapeutic Target in Hypertrophic Cardiomyopathy. 

Tubulin Detyrosination: An Emerging Therapeutic Target in Hypertrophic Cardiomyopathy. 

Margulies KB, Prosser BL.

Circ Heart Fail. 2021 Jan;14(1):e008006. doi: 10.1161/CIRCHEARTFAILURE.120.008006. Epub 2021 Jan 12. PMID: 33430601
Heart Failure Mechanobiology

Depletion of Vasohibin 1 Speeds Contraction and Relaxation in Failing Human Cardiomyocytes.

Depletion of Vasohibin 1 Speeds Contraction and Relaxation in Failing Human Cardiomyocytes. 

Chen CY, Salomon AK, Caporizzo MA, Curry S, Kelly NA, Bedi K, Bogush AI, Krämer E, Schlossarek S, Janiak P, Moutin MJ, Carrier L, Margulies KB, Prosser BL.

Circ Res. 2020 Jul 3;127(2):e14-e27. doi: 10.1161/CIRCRESAHA.119.315947. Epub 2020 Apr 10. PMID: 32272864
Heart Failure Mechanobiology

Microtubules Increase Diastolic Stiffness in Failing Human Cardiomyocytes and Myocardium. 

Microtubules Increase Diastolic Stiffness in Failing Human Cardiomyocytes and Myocardium. 

Caporizzo MA, Chen CY, Bedi K, Margulies KB, Prosser BL.

Circulation. 2020 Mar 17;141(11):902-915. doi: 10.1161/CIRCULATIONAHA.119.043930. Epub 2020 Jan 16. PMID: 31941365
Mechanobiology Heart Failure

A Balance Between Intermediate Filaments and Microtubules Maintains Nuclear Architecture in the Cardiomyocyte. 

A Balance Between Intermediate Filaments and Microtubules Maintains Nuclear Architecture in the Cardiomyocyte. 

Heffler J, Shah PP, Robison P, Phyo S, Veliz K, Uchida K, Bogush A, Rhoades J, Jain R, Prosser BL.

Circ Res. 2020 Jan 31;126(3):e10-e26. doi: 10.1161/CIRCRESAHA.119.315582. Epub 2019 Dec 11. PMID: 31822208
Mechanobiology

Cardiac microtubules in health and heart disease. 

Cardiac microtubules in health and heart disease. 

Caporizzo MA, Chen CY, Prosser BL.

Exp Biol Med. 2019 Nov;244(15):1255-1272. doi: 10.1177/1535370219868960. Epub 2019 Aug 9. PMID: 31398994  Review.
Mechanobiology RNA Biology Heart Failure

Mechanosensing by the Lamina Protects against Nuclear Rupture, DNA Damage, and Cell-Cycle Arrest. 

Mechanosensing by the Lamina Protects against Nuclear Rupture, DNA Damage, and Cell-Cycle Arrest. 

Cho S, Vashisth M, Abbas A, Majkut S, Vogel K, Xia Y, Ivanovska IL, Irianto J, Tewari M, Zhu K, Tichy ED, Mourkioti F, Tang HY, Greenberg RA, Prosser BL, Discher DE.

Dev Cell. 2019 Jun 17;49(6):920-935.e5. doi: 10.1016/j.devcel.2019.04.020. Epub 2019 May 16. PMID: 31105008
Mechanobiology

Microtubules Provide a Viscoelastic Resistance to Myocyte Motion. 

Microtubules Provide a Viscoelastic Resistance to Myocyte Motion. 

Caporizzo MA, Chen CY, Salomon AK, Margulies KB, Prosser BL.

Biophys J. 2018 Nov 6;115(9):1796-1807. doi: 10.1016/j.bpj.2018.09.019. Epub 2018 Sep 28. PMID: 30322798
Mechanobiology

Suppression of detyrosinated microtubules improves cardiomyocyte function in human heart failure. 

Suppression of detyrosinated microtubules improves cardiomyocyte function in human heart failure. 

Chen CY, Caporizzo MA, Bedi K, Vite A, Bogush AI, Robison P, Heffler JG, Salomon AK, Kelly NA, Babu A, Morley MP, Margulies KB, Prosser BL.

Nat Med. 2018 Aug;24(8):1225-1233. doi: 10.1038/s41591-018-0046-2. Epub 2018 Jun 11. PMID: 29892068
Mechanobiology Heart Failure

Microtubule mechanics in the working myocyte. 

Microtubule mechanics in the working myocyte. 

Robison P, Prosser BL.

J Physiol. 2017 Jun 15;595(12):3931-3937. doi: 10.1113/JP273046. Epub 2017 Mar 9.PMID: 28116814. Review.
Mechanobiology Heart Failure

Mechanical signaling coordinates the embryonic heartbeat. 

Mechanical signaling coordinates the embryonic heartbeat. 

Chiou KK, Rocks JW, Chen CY, Cho S, Merkus KE, Rajaratnam A, Robison P, Tewari M, Vogel K, Majkut SF, Prosser BL, Discher DE, Liu AJ.

Proc Natl Acad Sci U S A. 2016 Aug 9;113(32):8939-44. doi: 10.1073/pnas.1520428113. Epub 2016 Jul 25. PMID: 27457951
Mechanobiology

Detyrosinated microtubules buckle and bear load in contracting cardiomyocytes. 

Detyrosinated microtubules buckle and bear load in contracting cardiomyocytes. 

Robison P, Caporizzo MA, Ahmadzadeh H, Bogush AI, Chen CY, Margulies KB, Shenoy VB, Prosser BL.

Science. 2016 Apr 22;352(6284):aaf0659. doi: 10.1126/science.aaf0659.

PMID: 27102488

Heart Failure Mechanobiology

Modeling Local X-ROS and Calcium Signaling in the Heart. 

Modeling Local X-ROS and Calcium Signaling in the Heart. 

Limbu S, Hoang-Trong TM, Prosser BL, Lederer WJ, Jafri MS.

Biophys J. 2015 Nov 17;109(10):2037-50. doi: 10.1016/j.bpj.2015.09.031. PMID: 26588563
Mechanobiology

Detyrosinated microtubules modulate mechanotransduction in heart and skeletal muscle. 

Detyrosinated microtubules modulate mechanotransduction in heart and skeletal muscle. 

Kerr JP, Robison P, Shi G, Bogush AI, Kempema AM, Hexum JK, Becerra N, Harki DA, Martin SS, Raiteri R, Prosser BL, Ward CW.

Nat Commun. 2015 Oct 8;6:8526. doi: 10.1038/ncomms9526. PMID: 26446751
Heart Failure Mechanobiology

Contractile Function During Angiotensin-II Activation: Increased Nox2 Activity Modulates Cardiac Calcium Handling via Phospholamban Phosphorylation. 

Contractile Function During Angiotensin-II Activation: Increased Nox2 Activity Modulates Cardiac Calcium Handling via Phospholamban Phosphorylation. 

Zhang M, Prosser BL, Bamboye MA, Gondim ANS, Santos CX, Martin D, Ghigo A, Perino A, Brewer AC, Ward CW, Hirsch E, Lederer WJ, Shah AM.

J Am Coll Cardiol. 2015 Jul 21;66(3):261-272. doi: 10.1016/j.jacc.2015.05.020.

PMID: 26184620

Heart Failure Mechanobiology

Myosin-binding protein C corrects an intrinsic inhomogeneity in cardiac excitation-contraction coupling. 

Myosin-binding protein C corrects an intrinsic inhomogeneity in cardiac excitation-contraction coupling. 

Previs MJ, Prosser BL, Mun JY, Previs SB, Gulick J, Lee K, Robbins J, Craig R, Lederer WJ, Warshaw DM.

Sci Adv. 2015;1(1):e1400205. doi: 10.1126/sciadv.1400205. PMID: 25839057
Heart Failure Mechanobiology

Mechano-chemo transduction tunes the heartstrings. 

Mechano-chemo transduction tunes the heartstrings. 

Prosser BL, Ward CW.

Sci Signal. 2014 Mar 18;7(317):pe7. doi: 10.1126/scisignal.2005214.

PMID: 24643798

Mechanobiology

Mechanical stretch-induced activation of ROS/RNS signaling in striated muscle. 

Mechanical stretch-induced activation of ROS/RNS signaling in striated muscle. 

Ward CW, Prosser BL, Lederer WJ.

Antioxid Redox Signal. 2014 Feb 20;20(6):929-36. doi: 10.1089/ars.2013.5517. Epub 2014 Jan 3. PMID: 23971496
Mechanobiology

X-ROS signalling is enhanced and graded by cyclic cardiomyocyte stretch. 

X-ROS signalling is enhanced and graded by cyclic cardiomyocyte stretch. 

Prosser BL, Ward CW, Lederer WJ.

Cardiovasc Res. 2013 May 1;98(2):307-14. doi: 10.1093/cvr/cvt066. Epub 2013 Mar 21. PMID: 23524301
Mechanobiology

X-ROS signaling in the heart and skeletal muscle: stretch-dependent local ROS regulates [Ca²⁺]i. 

X-ROS signaling in the heart and skeletal muscle: stretch-dependent local ROS regulates [Ca²⁺]i. 

Prosser BL, Khairallah RJ, Ziman AP, Ward CW, Lederer WJ.

J Mol Cell Cardiol. 2013 May;58:172-81. doi: 10.1016/j.yjmcc.2012.11.011. Epub 2012 Dec 6. PMID: 23220288
Mechanobiology

Microtubules underlie dysfunction in duchenne muscular dystrophy. 

Microtubules underlie dysfunction in duchenne muscular dystrophy. 

Khairallah RJ, Shi G, Sbrana F, Prosser BL, Borroto C, Mazaitis MJ, Hoffman EP, Mahurkar A, Sachs F, Sun Y, Chen YW, Raiteri R, Lederer WJ, Dorsey SG, Ward CW.

Sci Signal. 2012 Aug 7;5(236):ra56. doi: 10.1126/scisignal.2002829.

PMID: 22871609

Mechanobiology

X-ROS signaling: rapid mechano-chemo transduction in heart. 

X-ROS signaling: rapid mechano-chemo transduction in heart. 

Prosser BL, Ward CW, Lederer WJ.

Science. 2011 Sep 9;333(6048):1440-5. doi: 10.1126/science.1202768. PMID: 21903813
Heart Failure Mechanobiology