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Shared and distinct mechanisms of skeletal muscle atrophy: A narrative review
Journal article   Peer reviewed

Shared and distinct mechanisms of skeletal muscle atrophy: A narrative review

Dylan Wilburn, Ahmed Ismaeel, Steven Machek, Emma Fletcher and Panagiotis Koutakis
Ageing research reviews, Vol.71, 101463
11/2021
DOI: https://doi.org/10.1016/j.arr.2021.101463
PMID: 34534682
Web of Science ID: WOS:000700925300005

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Abstract

Maintenance of skeletal muscle mass and function is an incredibly nuanced balance of anabolism and catabolism that can become distorted within different pathological conditions. In this paper we intend to discuss the distinct intracellular signaling events that regulate muscle protein atrophy for a given clinical occurrence. Aside from the common outcome of muscle deterioration, several conditions have at least one or more distinct mechanisms that creates unique intracellular environments that facilitate muscle loss. The subtle individuality to each of these given pathologies can provide both researchers and clinicians with specific targets of interest to further identify and increase the efficacy of medical treatments and interventions. Above shows varying signaling pathways that regulate both skeletal muscle anabolism and catabolism. Focal Adhesion Kinase (FAK) is shown activate mammalian target of rapamycin (mTOR) in response to mechanical load through the phosphatidylinositol 3 kinase (PI3K), protein kinase B (AKT) pathway. Insulin or insulin-like growth factor (IGF) stimulation can activate mTOR through the same cascade. Also shown are the catabolic pathways related to inflammatory cytokines such as tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6). TNF-α receptor 1 (TNFR1) ligand binding activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and c-Jun N-terminal kinase (JNK) pathway increasing rates of proteolysis. Protein Kinase R (PKR) can also stimulate the activation of NF-kB. IL-6 receptor binding activates the Janus Kinase (JAK) Signal Transducer and Activator of Transcription (STAT) signaling that can increase rates of muscle loss. Transforming Growth Factor-beta (TGF-β) receptor binding facilitates small mothers against decapentaplegic (SMAD) homologs 2 and 3 (SMAD2/3) phosphorylation, and subsequent SMAD 4 phosphorylation, upregulating genes related to collagen synthesis and fibrosis. Additionally, glucocorticoid (GC) receptor activation, dimerization, and DNA binding subsequently facilitates increases in FOXO expression which can increase the expression of UPS related E3 ligases. During low energy availability, increased 5' adenosine monophosphate-activated protein kinase (AMPK)-Unc-51 like autophagy activating kinase 1 (ULK1) phosphorylation induces the activation of autophagy related processes.

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