MSGID: 1:317/3 64080f7b   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    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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