Revisiting the Role of GSK3, A Modulator of Innate Immunity, in Idiopathic Inclusion Body Myositis

Abstract

Idiopathic or sporadic inclusion body myositis (IBM) is the leading age-related (onset >50 years of age) autoimmune muscular pathology, resulting in significant debilitation in affected individuals. Once viewed as primarily a degenerative disorder, it is now evident that much like several other neuro-muscular degenerative disorders, IBM has a major autoinflammatory component resulting in chronic inflammation-induced muscle destruction. Thus, IBM is now considered primarily an inflammatory pathology. To date, there is no effective treatment for sporadic inclusion body myositis, and little is understood about the pathology at the molecular level, which would offer the best hopes of at least slowing down the degenerative process. Among the previously examined potential molecular players in IBM is glycogen synthase kinase (GSK)-3, whose role in promoting TAU phosphorylation and inclusion bodies in Alzheimer’s disease is well known. This review looks to re-examine the role of GSK3 in IBM, not strictly as a promoter of TAU and Abeta inclusions, but as a novel player in the innate immune system, discussing some of the recent roles discovered for this well-studied kinase in inflammatory-mediated pathology.

Inclusion body myositis, viral infections, and TDP-43: a narrative review

“…Also, the glycogen synthase kinase 3 (GSK3), a serine/threonine kinase with 2 isoforms (α and β), is activated in IBM [ 33 ]. GSK3, involved in many cellular processes, is an immunomodulator in IBM [ 33 ].…”

“…Also, the glycogen synthase kinase 3 (GSK3), a serine/threonine kinase with 2 isoforms (α and β), is activated in IBM [ 33 ]. GSK3, involved in many cellular processes, is an immunomodulator in IBM [ 33 ]. GSK3 delays and decreases IFN-1 production, enhances IFNγ signaling, but also increases and delays pro-inflammatory cytokines production [ 33 ].…”

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“…In this signaling cascade, AKT can phosphorylate and activate mTOR, thereby promoting protein synthesis [27]. At the same time, active AKT [28] leads to the inhibition of glycogen synthase kinase 3 (GSK-3), a metabolic kinase whose aberrant activity has been linked to inflammatory-mediated muscle decay, by phosphorylating GSK-3 on Ser21/Ser9 (-α/-β) [29]. The GSK-3β isoform, which is more expressed in skeletal muscle than the α-isoform [30], is considered a negative regulator of protein synthesis, and its ablation seems to favor atrophied skeletal muscle regeneration [29].…”

“…At the same time, active AKT [28] leads to the inhibition of glycogen synthase kinase 3 (GSK-3), a metabolic kinase whose aberrant activity has been linked to inflammatory-mediated muscle decay, by phosphorylating GSK-3 on Ser21/Ser9 (-α/-β) [29]. The GSK-3β isoform, which is more expressed in skeletal muscle than the α-isoform [30], is considered a negative regulator of protein synthesis, and its ablation seems to favor atrophied skeletal muscle regeneration [29]. In fact, since active GSK-3β stimulates atrogin-1 and MuRF1 expression, two enzymes involved in UPS-mediated protein breakdown [31,32], it is not surprising that the lack or loss of GSK-3β prevents muscle mass and myofibrillar loss during atrophic conditions.…”

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“…These include the phosphoinositide 3-kinase/Akt (PI3K/Akt) pathway, MAPK pathway, NFκB, and activator protein-1 (AP-1) transcription factors [8][9][10]. The activity of GSK3 is strictly regulated through several phosphorylation sites including inhibitory serinephosphorylation mediated by Akt, protein kinase A or protein kinase C at serine-21 and serine-9 in GSK3α and β, respectively [8,11]. Conversely, when phosphorylated at the active tyrosine sites 279-GSK3α and 216-GSK3β within the catalytic domain, GSK3 interacts with and is responsible for the activation of a number of downstream pro-inflammatory signals, ultimately supporting the production and release of a plethora of pro-inflammatory mediators [8][9][10][11].…”