Cardiomyocytes

Natural pacemakers

Credit: Art by Nelly Aghekyan. Set in motion by Dr. Emanuele Petretto. Words by Dr. Masia Maksymowicz. Project Coordinator: Dr. Masia Maksymowicz, Series Director: Dr. Radhika Patnala Sci-Illustrate, Endosymbiont

#Extraordinarycelltypes #sciart #lifescience #heart #cardiomyocytes

The short history and evolution of the heart

Although the brain is the main control centre of our bodies, humans always believed that the most important organ is the heart. In ancient Egypt, people believed that after death their heart will be weighed. The heart of a good person would be lighter than a feather, giving them a passage to a paradise (1). The oldest painting of the heart can be found in El Pindal Cave, Spain, dating from 15,000 years ago, possibly representing life and death (1). In the Bible, the heart is the place where we store our emotions and soul (1).

Indeed, the heart is irreplaceable. It is the first organ formed in a developing fetus (2). As mammals, humans have only one heart; however some organisms have more. Cephalopods (for example octopus) have three of them: two that pump the blood to the gills, where it gets oxygenated, and the third one responsible for the movement of the blood across the body (3). On the other hand, corrals, jellyfish and starfish are heartless (starfish actually don’t even have blood!) (3).

What makes our heart beat?

Let’s focus on the human heart. Simply looking, it is a pump used to move the blood throughout the body. This allows it to constantly deliver oxygen to the cells. It is possible thanks to four chambers: right and left atriums (thin-walled, receiving blood), and right and left ventricles (thick-walled, pumping blood out of the heart) (4). What makes this pump unique is its cardiac pacemaker and conduction system (4), which, among others, contain pacemaker cells, which are a specialised type of cardiomyocytes.

Cardiomyocytes (or cardiac muscle cells) are a type of muscle cells that form the heart. Unlike skeletal muscles, they work under involuntary control. Each cardiac cell is branched, with a single, centrally-located nucleus, and multiple mitochondria, which are responsible for generating the energy of these energy-demanding cells. What makes them different from skeletal cells is the sarcolemma, a cell membrane that surrounds the cell nucleus. Inside this membrane, there are multiple voltage-gated calcium channels (5). Another important feature, multiple mitochondria, is especially important for this never-stopping organ. In fact, mitochondria account for about 35% of heart tissue — that’s about 10 times more than in skeletal muscles! Cardiomyocytes’ mitochondria are responsible for making up to 90% of energy in the resting mode (6).

So, what exactly makes our hearts beat? Astonishingly, it is the cardiomyocytes which single-handedly are responsible for generating contractile force in the intact heart (2, 5). When working together, cardiac cells are responsible for creating the basal heartbeat (2). In fact, when isolated from the heart and put on a Petri dish, single cardiac muscle cells continue to pulsate.

The heart of the matter

Unlike some other cells, cardiomyocytes have limited regenerative abilities, making heart damage or diseases challenging to repair (7). On the other hand, cardiomyocytes can adapt to varying workloads by changing their size and structure, a phenomenon called cardiac remodelling (8). This process occurs in response to cardiac diseases or damage (e.g. due to a heart attack or high blood pressure).

Recent studies focus on understanding the role of mitochondria in cardiomyocytes and how their dysfunction contributes to the development of heart diseases (9). Since mitochondria are responsible for cellular metabolism, supplying the cells with energy from cellular respiration, any issues with them result in decreased amounts of energy and increased amounts of reactive oxygen species (ROS). ROS in turn can cause mutations in both nuclear and mitochondrial DNA which can lead to more complex metabolic diseases (9). These genetic defects could be reversed using CRISPR-Cas9 genome editing (10). Scientists are working on using CRISPR-Cas9 to fight congenital heart disease (CHD), which is caused by genetic modifications (11, 12). However, we will have to wait a little longer before the CRISPR-Cas9-based therapeutics become available.

Recognizing and appreciating the labs working in this space:

• Sinha Lab, Wellcome-MRC Cambridge Stem Cell Institute, UK, https://www.sinha-lab.org/, Twitter: @LabSinha
• Winata Lab, Zebrafish Developmental Genomics Laboratory, IIMCB, Poland, www: zdglab.iimcb.gov.pl, Twitter: @ZebraFishLab
• Cardiac Cell Physiology Laboratory, University of Missouri, https://medicine.missouri.edu/centers-institutes-labs/cardiac-cell-physiology-lab
• Bakkers group, Hubrecht Institute, Netherlands, https://www.hubrecht.eu/research-groups/bakkers-group/, Twitter: @J_Bakkers
• Riley Group, University of Oxford, UK, https://www.dpag.ox.ac.uk/research/riley-group, Twitter: @GroupRiley
• Cardiomyocyte Renewal Laboratory, Texas Heart Institute, USA, https://www.texasheart.org/research/cardiomyocyte-renewal-laboratory/, Twitter: @Texas_Heart
• The Hong Laboratory, University of Utah, USA, https://cvrti.utah.edu/the-hong-laboratory/, Twitter: @NEH_CVRTI
• Lee Lab, Harvard Department of Stem Cell and Regenerative Biology, Harvard University, USA, https://hscrb.harvard.edu/labs/lee-lab/about/, Twitter: @HSCRB
• Bernardo Lab, National Heart & Lung Institute, Imperial College London, UK, https://www.imperial.ac.uk/people/a.bernardo, Twitter: @ImperialNHLI
• Jay Zhang Lab, Heersink School of Medicine, The University of Alabama at Birmingham, https://sites.uab.edu/jayzhanglab/cardiac-cell-engineering/, Twitter: @uabbme

References:

1. Figueredo, V. The Ancient Heart: What the Heart Meant to Our Ancestors. J Am Coll Cardiol. 2021 Aug, 78 (9) 957–959. https://doi.org/10.1016/j.jacc.2021.06.041
2. Woodcock, Elizabeth A, and Scot J Matkovich. “Cardiomyocytes structure, function and associated pathologies.” The international journal of biochemistry & cell biology vol. 37,9 (2005): 1746–51. doi:10.1016/j.biocel.2005.04.011
3. Alibhai A, Stanford K, Rutland S and Rutland C (2020) Hearts, and the Heartless, in the Animal Kingdom. Front. Young Minds. 8:540440. doi: 10.3389/frym.2020.540440
4. SEER Training Modules, Structure of the Heart. U. S. National Institutes of Health, National Cancer Institute. 11/12/2023 <https://training.seer.cancer.gov/>.
5. Ripa R, George T, Shumway KR, et al. Physiology, Cardiac Muscle. [Updated 2023 Jul 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK572070/
6. Park, Song-Young et al. “Cardiac, skeletal, and smooth muscle mitochondrial respiration: are all mitochondria created equal?.” American journal of physiology. Heart and circulatory physiology vol. 307,3 (2014): H346–52. doi:10.1152/ajpheart.00227.2014
7. du Pré, Bastiaan C et al. “Stem cells for cardiac repair: an introduction.” Journal of geriatric cardiology : JGC vol. 10,2 (2013): 186–97. doi:10.3969/j.issn.1671–5411.2013.02.003
8. Azevedo, Paula S et al. “Cardiac Remodeling: Concepts, Clinical Impact, Pathophysiological Mechanisms and Pharmacologic Treatment.” Arquivos brasileiros de cardiologia vol. 106,1 (2016): 62–9. doi:10.5935/abc.20160005
9. Stamerra, Cosimo Andrea et al. “Mitochondrial Dysfunction and Cardiovascular Disease: Pathophysiology and Emerging Therapies.” Oxidative medicine and cellular longevity vol. 2022 9530007. 2 Aug. 2022, doi:10.1155/2022/9530007
10. Motta, Benedetta M et al. “The Impact of CRISPR/Cas9 Technology on Cardiac Research: From Disease Modelling to Therapeutic Approaches.” Stem cells international vol. 2017 (2017): 8960236. doi:10.1155/2017/8960236
11. Seok, Heeyoung et al. “Application of CRISPR-Cas9 gene editing for congenital heart disease.” Clinical and experimental pediatrics vol. 64,6 (2021): 269–279. doi:10.3345/cep.2020.02096
12. Liu, Ning, and Eric N Olson. “CRISPR Modeling and Correction of Cardiovascular Disease.” Circulation research vol. 130,12 (2022): 1827–1850. doi:10.1161/CIRCRESAHA.122.320496

About the author:

DR. MAŁGORZATA ‘MASIA’ MAKSYMOWICZ

Content Editor The League of Extraordinary Cell Types, Sci-Illustrate Stories

Dr. Maksymowicz did her Ph.D. in Cell Biology (IIMCB, Poland) studying the intracellular trafficking and inflammatory signalling of a cytokine receptor. She did a 1-year post-doc at Nencki Institute, Poland, studying the protein- and RNA-binding properties of proteins. Currently, she is doing a post-doc at Barts Cancer Institute, UK, studying the links between endocytosis and tumorigenesis. Dr. Maksymowicz is passionate about science and loves to combine different fields of biology, always trying to seek beauty in nature.

About the artist:

NELLY AGHEKYAN

Contributing Artist The League of Extraordinary Cell Types, Sci-Illustrate Stories

Nelli Aghekyan, did a bachelor’s and master’s in Architecture in Armenia, after studying architecture and interior design for 6 years, she concentrated on her drawing skills and continued her path in the illustration world. She works mainly on children’s book illustrations, some of her books are now being published. Currently living in Italy, she works as a full-time freelance artist, collaborating with different companies and clients.

About the animator:

DR. EMANUELE PETRETTO

Animator The League of Extraordinary Cell Types, Sci-Illustrate Stories

Dr. Petretto received his Ph.D. in Biochemistry at the University of Fribourg, Switzerland, focusing on the behavior of matter at nanoscopic scales and the stability of colloidal systems. Using molecular dynamics simulations, he explored the delicate interaction among particles, interfaces, and solvents.

Currently, he is fully pursuing another delicate interaction: the intricate interplay between art and science. Through data visualization, motion design, and games, he wants to show the wonders of the complexity surrounding us.

https://linktr.ee/p3.illustration

About the series:

The League of Extraordinary Cell types

The team at Sci-Illustrate and Endosymbiont bring to you an exciting series where we dive deep into the wondrous cell types in our body, that make our hearts tick ❤.

Sci-Illustrate, Endosymbiont