Heart toggles between maintenance and energy-boost mode using ribosomes
New mechanism found which can be exploited to prevent or heal damage to
the heart

Date:
March 7, 2023
Source:
Center for Genomic Regulation
Summary:
Researchers reveal that cardiomyocytes and skeletal muscle cells
replace their existing stock of ribosomes with a different type
which can make physical contact with mitochondria, the batteries
of the cells, and significantly boost the production of ATP. In the
heart, the natural mechanism is triggered in response to myocardial
infarction, as well as cardiac hypertrophy. The findings establish
ribosomes as a new frontier for therapeutic strategies that prevent
or heal damage to the heart.


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FULL STORY ========================================================================== Researchers at the Centre for Genomic Regulation (CRG) in Barcelona
have discovered a mechanism involving ribosomes which helps the heart
toggle between a 'regular maintenance mode' for day-to-day function and
an 'energy-boost mode' which aids recovery for high-demand situations
including heart attacks. The findings are published in a 'Breakthrough
Article' in the journal Nucleic Acids Research.


========================================================================== Ribosomes are the molecular factories that manufacture proteins in all
living cells. Historically, they have been perceived as simple but vital workhorses which lack the ability to regulate a cell's function. However,
there is increasing evidence that these fundamental units -- which come
in different shapes and forms -- carry out specialised tasks, which are
yet to be discovered.

Using different experimental techniques and latest-generation sequencing technologies, the researchers found that cardiomyocytes, the cells
responsible for the heart contracting, and skeletal muscle cells, which
are connected to bones and are critical for strength and movement,
have different types of ribosomes compared to all other types of cells
in the body.

"For a long time, we thought that ribosomes were the same in every single
cell of the human body. This makes them impractical drug targets as you
could be healing one body part while damaging many others. The existence
of specialised ribosomes and their specificity to heart and muscle cells
is a turning point because it means it is possible to develop medicines
that target specific ribosomes for the purpose of treating cardiovascular disease," explains Dr. Eva Novoa, corresponding author of the study and researcher at the Centre for Genomic Regulation.

Ribosomes are made of proteins. While the ribosomes in most human cells
contain ribosomal protein L3 (RPL3), the ribosomes in cardiomyocytes
and skeletal muscle cells contain ribosomal protein L3-like (RPL3L). The crucial difference between the proteins, which share 77% of their amino
acid sequence, is their tail. The study shows that cells will exclusively
use one protein or the other.

Whichever protein ends up being used, the corresponding tail sticks
out on the surface of the ribosome, changing its shape and surface,
which in turn affects how it binds to other proteins and receptors.

The researchers found that cardiomyocyte and skeletal muscle ribosomes
showed no benefit in terms of protein synthesis compared to other
ribosomes. However, the researchers were surprised to find that knocking
the RPL3L gene out in mice showed both cardiomyocytes and skeletal
muscle cells creating ribosomes with RPL3 instead. In stark contrast,
knocking out RPL3 was lethal.

Researchers found that this newfound compensation mechanism also naturally occurred in response to a heart attack or myocardial infarction, with cardiomyocytes replacing all their existing stock of RPL3L-containing
ribosomes with ribosomes containing RPL3 instead. The different shape of
the new ribosomes enables them to make physical contact with mitochondria,
the batteries of the cells, and significantly boosts the production of
ATP, the universal currency used for energy. The effect was detected
within six hours after infarction and peaked after 72 hours.

This ribosome replacement mechanism also occurs during cardiac
hypertrophy, a response of the heart to increased workload which can
be either physiological, such as after exercise, or pathological, due
to disease. RPL3-containing ribosomes in cardiomyocytes peak after 96
hours in response to cardiac hypertrophy.

The study provides some clues for why the heart and muscle use RPL3L for ribosomes in the first place. The researchers found that RPL3L is only
present in the ribosomes of adult cardiomyocytes, while fetal tissues exclusively use RPL3. At the same time, mice lacking RPL3L had lower
lean muscle mass at 55- weeks old compared to mice with RPL3L.

"When we are born, our hearts need lots of energy to grow. At this point, cardiomyocytes only express RPL3, swapping to RPL3L only once the heart
is fully mature. We don't know exactly why, but the cells could be making
the switch to fine tune the mitochondrial activity in resting conditions
and possibly decrease levels of free radicals, dangerous by-products of mitochondrial metabolism. This could explain how the heart delicately
balances two different modes -- one where ribosomes boost energy levels
and one where the heart is kept in maintenance mode," explains first
author of the study and PhD candidate Ivan Milenkovic.

The discovery of this mechanism can be exploited to improve cardiac
health and function, and establishes ribosomes as a new frontier for therapeutic strategies that prevent or heal damage to the heart. The researchers are now researching the molecular mechanisms in further
detail to distinguish pathological and physiological cardiac hypertrophy, including exercise experiments with mice to assess how the presence or
absence of RPL3L in cardiomyocytes affects physical performance.

* RELATED_TOPICS
o Health_&_Medicine
# Heart_Disease # Stem_Cells # Stroke_Prevention #
Fitness # Cholesterol # Vioxx # Human_Biology #
Diseases_and_Conditions
* RELATED_TERMS
o Artificial_heart o Defibrillation o Heart_rate o CPR o
Ischaemic_heart_disease o Artery o Coronary_heart_disease
o Heart

========================================================================== Story Source: Materials provided by Center_for_Genomic_Regulation. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Ivan Milenkovic, Helaine Graziele Santos Vieira, Morghan C Lucas,
Jorge
Ruiz-Orera, Giannino Patone, Scott Kesteven, Jianxin Wu, Michael
Feneley, Guadalupe Espadas, Eduard Sabido', Norbert Hu"bner,
Sebastiaan van Heesch, Mirko Vo"lkers, Eva Maria Novoa. Dynamic
interplay between RPL3- and RPL3L-containing ribosomes modulates
mitochondrial activity in the mammalian heart. Nucleic Acids
Research, 2023 DOI: 10.1093/nar/gkad121 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/03/230307144344.htm

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