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The Pathogenesis of Physical Frailty and Sarcopenia

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Frailty and Sarcopenia in Cirrhosis

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Abstract

Disordered energy metabolism in cirrhosis contributes to skeletal muscle proteolysis and impaired protein synthesis with dysregulated protein homeostasis (proteostasis) and resultant sarcopenia. Circulating abnormalities including hyperammonemia, hypogonadism, decreased branched chain amino acids, and endotoxemia are potential mediators of the liver-muscle axis. Etiology of liver disease including ethanol and fatty acids also directly affects muscle proteostasis. Transcriptional upregulation of myostatin via ammonia-induced activation of p65NFKB impairs signaling by the protein homeostasis regulatory molecule, mammalian target of rapamycin complex 1 (mTORC1). The recently described hyperammonemic stress response (HASR) is characterized by activation of an amino acid sensor, general control non-derepressible 2 (GCN2) with persistent phosphorylation of eIF2α with reduction in protein synthesis. Hyperammonemia of cirrhosis also increases autophagic proteolysis and mitochondrial dysfunction with cataplerosis. Targeting mediators of the liver-muscle axis, the signaling perturbations in the muscle, and strategies to restore metabolic homeostasis with ammonia-lowering, anaplerotic agents and myostatin antagonists have the potential to be novel and effective therapies to reverse sarcopenia in cirrhosis.

Supported in part by: NIH RO1 GM119174; RO1 DK 113196; P50 AA024333; R21 AR 71046; U01AA026976; UO1 DK 061732 and Mikati Foundation.

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Authors and Affiliations

  1. Department of Gastroenterology, Hepatology, Cleveland Clinic, Cleveland, OH, USA

    Srinivasan Dasarathy

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  1. Srinivasan Dasarathy
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  1. Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, AB, Canada

    Puneeta Tandon

  2. Division of Gastroenterology and Liver Unit, University of Alberta, Edmonton, AB, Canada

    Aldo J. Montano-Loza

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Dasarathy, S. (2020). The Pathogenesis of Physical Frailty and Sarcopenia. In: Tandon, P., Montano-Loza, A. (eds) Frailty and Sarcopenia in Cirrhosis. Springer, Cham. https://doi.org/10.1007/978-3-030-26226-6_4

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