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The regulation of protein synthesis in heart muscle under normal conditions and in the adriamycin-cardiomyopathy

Die Regulation der Herzmuskel-Proteinsynthese unter normalen Bedingungen und bei der Adriamycin-Kardiomyopathie

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Summary

The regulation of cardiac protein synthesis, in particular messenger-RNA (mRNA) and polyribosome metabolism, has been investigated in normal rat heart muscle and in the adriamycin-cardiomyopathy by using newly developed methods for the isolation, characterization and in-vitro translation of cardiac polyribosomes and mRNA. The obtained data allow the following conclusions:

  1. 1.

    Normal heart muscle has a high content of polyribosomes (865 µg/g) and of mRNA (20–60 µg/g), and thus a high rate of protein synthesis.

  2. 2.

    The level of cardiac polyribosomes and mRNA is strictly age-dependent and much higher in young animals (2–3 ×). This corresponds to a higher cardiac protein synthesis rate in young animals with a growing heart muscle, and shows that the protein-synthetic reserves of heart muscle decrease sharply with age.

  3. 3.

    Withdrawal of food for 1–3 days results in a pronounced decrease (−50% to −70%) of cardiac polyribosomes and mRNA, demonstrating that the cardiac protein synthesis reacts very sensitively to conditions of starving.

  4. 4.

    The cardiac polyribosomes and mRNA are unevenly distributed in the myocyte. The bulk of these substances is present in the cardiac microsomes, and much less is found in nuclei, myofibrils, mitochondria and in the post-microsomal fraction (=cell-sap) of the cardiac muscle. This shows that the major intracellular site of cardiac protein synthesis is the microsomal fraction of the myocyte.

  5. 5.

    A pool of untranslated mRNA was demonstrated to be present in the cell-sap of the myocyte. This mRNA is to some extent translatable in-vitro and appears to represent mRNA sub-pools with two functions: a) mRNA which is partially broken down or in the process of being broken down, and b) intact mRNA which could have a “reserve-function”, e.g., by being utilized to increase cardiac protein synthesis under certain conditions.

  6. 6.

    A method of quantitating small amounts of cardiac mRNA (25–50 ng) has been developed which makes it possible to estimate the mRNA content of cardiac biopsies.

  7. 7.

    These methods were utilized to study the relevance of changes in RNA- and protein synthesis in the development of the adriamycin-cardiomyopathy. It appears that severe decreases in cardiac mRNA and polyribosome levels are a key factor in the pathogenesis of the adriamycin-cardiomyopathy. These decreases are probably caused by the direct binding of adriamycin to cardiac DNA and lead themselves to a persisting decrease in cardiac protein synthesis which in view of the short half-lives of the cardiac contractile proteins (5–12 days) causes a gradual loss of cardiac structure and function.

Zusammenfassung

Die Regulation der myokardialen Proteinsynthese, insbesondere der Messenger-RNS (mRNS) und Polyribosomen Metabolismus, wurden in normalem Rattenherzmuskel und in der Adriamycin-Kardiomyopathie untersucht. Dabei wurden neu-entwickelte Methoden zur Isolierung, Charakterisierung und in-vitro Translation myokardialer Polyribosomen und mRNS eingesetzt. Die erhaltenen Ergebnisse erlauben folgende Folgerungen:

  1. 1.

    Normaler Herzmuskel hat einen hohen Gehalt an Polyribosomen und mRNS und daher eine hohe Proteinsyntheserate.

  2. 2.

    Der Gehalt des Herzmuskels an Polyribosomen und mRNS ist stark altersabhängig und wesentlich höher bei jungen Tieren (2–3×). Dies entspricht der höheren Proteinsyntheserate des wachsenden Herzmuskels junger Tiere und zeigt, daß die Proteinsynthesereserven des Herzmuskels mit steigendem Alter stark abnehmen.

  3. 3.

    Nahrungsentzug für 1–3 Tage führt zu einer ausgeprägten Abnahme (−50% bis −70%) der myokardialen Polyribosomen und mRNS und unterstreicht die Empfindlichkeit der Herzmuskel-Proteinsynthese hinsichtlich auch nur kurzer Hungerperioden.

  4. 4.

    Die intrazelluläre Verteilung der myokardialen Polyribosomen und mRNS ist sehr ungleichmäßig: Die große Mehrzahl dieser Substanzen befindet sich in der Mikrosomenfraktion des Herzmuskels; Zellkerne, Myofibrillen, Mitochondrien und der post-mikrosomale Überstand (=Zellsaft) enthalten nur jeweils geringe Mengen. Dies zeigt, daß der intrazelluläre Hauptort der myokardialen Proteinsynthese in der Mikrosomenfraktion des Herzmuskels liegt.

  5. 5.

    Ein Pool nicht-translatierter mRNS wurde von uns im Zellsaft des Herzmuskels nachgewiesen. Diese mRNS kann in-vitro teilweise translatiert werden und scheint sich aus zwei Fraktionen zusammenzusetzen: a) mRNS, die gerade abgebaut wird oder schon abgebaut ist, und b) intakte mRNS, die eine „Reserve-Funktion“ wahrnehmen könnte, z.B. durch Stimulierung der myokardialen Proteinsynthese unter bestimmten Bedingungen.

  6. 6.

    Durch eine neu-entwickelte Methode kann myokardiale mRNS in geringen Mengen (25–50 ng) quantifiziert werden. Dies eröffnet die Möglichkeit, den mRNS-Gehalt von Herzmuskelbiopsien zu bestimmen.

  7. 7.

    Diese Methoden wurden zur Überprüfung der Frage eingesetzt, inwieweit Veränderungen der RNS-und Proteinsynthese bei der Entstehung der Adriamycin-Kardiomyopathie eine Rolle spielen könnten. Unsere Daten lassen den Schluß zu, daß ausgeprägte Abnahmen der myokardialen mRNS- und Polyribosomenspiegel eine entscheidende Rolle bei der Pathogenese der Adriamycin-Kardiomyopathie spielen. Diese Abnahmen sind wahrscheinlich durch eine direkte Bindung von Adriamycin an die myokardiale DNS bedingt und führen ihrerseits zu einer persistierenden Abnahme der myokardialen Proteinsynthese, die aufgrund der kurzen Halbwertszeit der myokardialen Proteine (5–12 Tage) einen allmählichen Verlust der strukturellen und funktionellen Integrität des Myokards zur Folge hat.

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    J. Zähringer

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This paper is a concised review of the experiments presented at the VIIth European Congress of Cardiology (Paris, June 22–26, 1980) for the “Young Investigator's Price 1980” of the European Society of Cardiology

This study was supported by grants Za 58/3 and Za 58/5 from the Deutsche Forschungsgemeinschaft, and by grant Za 1 from the Wilhelm-Sander-Stiftung

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Zähringer, J. The regulation of protein synthesis in heart muscle under normal conditions and in the adriamycin-cardiomyopathy. Klin Wochenschr 59, 1273–1287 (1981). https://doi.org/10.1007/BF01711177

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