Activation of the ubiquitin-proteasome system contributes to oculopharyngeal muscular dystrophy through muscle atrophy

Abstract

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder characterized by progressive weakness and degeneration of specific muscles. OPMD is due to extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). Aggregation of the mutant protein in muscle nuclei is a hallmark of the disease. Previous transcriptomic analyses revealed the consistent deregulation of the ubiquitin-proteasome system (UPS) in OPMD animal models and patients, suggesting a role of this deregulation in OPMD pathogenesis. Subsequent studies proposed that UPS contribution to OPMD involved PABPN1 aggregation. Here, we use a Drosophila model of OPMD to address the functional importance of UPS deregulation in OPMD. Through genome-wide and targeted genetic screens we identify a large number of UPS components that are involved in OPMD. Half dosage of UPS genes reduces OPMD muscle defects suggesting a pathological increase of UPS activity in the disease. Quantification of proteasome activity confirms stronger activity in OPMD muscles, associated with degradation of myofibrillar proteins. Importantly, improvement of muscle structure and function in the presence of UPS mutants does not correlate with the levels of PABPN1 aggregation, but is linked to decreased degradation of muscle proteins. Oral treatment with the proteasome inhibitor MG132 is beneficial to the OPMD Drosophila model, improving muscle function although PABPN1 aggregation is enhanced. This functional study reveals the importance of increased UPS activity that underlies muscle atrophy in OPMD. It also provides a proof-of-concept that inhibitors of proteasome activity might be an attractive pharmacological approach for OPMD.

Diabetic Muscular Atrophy: Molecular Mechanisms and Promising Therapies

“…Muscle atrophy is closely related to two major protein degradation pathways, the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP). It is also related to the protein synthesis pathways, such as the insulin-like growth factor 1-phosphoinositide-3-kinase-Akt/protein kinase Bmammalian target of rapamycin (IGF1-PI3K-Akt/PKB-mTOR) pathway and IGF-1-AKT-Forkhead box O (FoxO) pathways (7)(8)(9)(10)(11)(12). In T2DM, insulin resistance has been shown to inhibit protein synthesis by inhibiting the IGF-1-PI3K-AKT/PKB-mTOR pathway, and to activate the UPS and ALP through the IGF-1-AKT-FoxO signaling pathway, thereby promoting muscle atrophy.…”

Clinical and mechanism advances of neuronal intranuclear inclusion disease

“…The existence of NIIs and the dysfunction of the ubiquitinproteasome system (UPS) are the shared pathological features in NIID and other neurodegenerative diseases. Similar to these neurodegenerative diseases, the impairment of the UPS, such as the increase of ubiquitinated proteins and P62 protein, is found in the pathological changes of NIID (Oh et al, 2015;Hagerman and Hagerman, 2021;Boivin and Charlet-Berguerand, 2022;Ogasawara et al, 2022;Ribot et al, 2022;Zhou et al, 2022). However, how expanded GGC repeats cause the formation of NIIs and dysfunction of the UPS is generally unknown in the pathogenesis of NIID.…”

Exogenous Antioxidants in Remyelination and Skeletal Muscle Recovery

“…The inhibition of these proteasomes causes protein oxidation and stimulates proapoptotic pathways [ 69 ]. Similarly, the proteasome mechanism in atrophy is related to the regulation of the ubiquitin-proteasome system by transcription factors including Nrf1 and Nrf2 [ 70 , 71 , 72 ]. In a model of oculopharyngeal muscular dystrophy using Drosophila the increased activity of the ubiquitin-proteasome system conducts to muscle damage and impaired function [ 71 ].…”

“…Similarly, the proteasome mechanism in atrophy is related to the regulation of the ubiquitin-proteasome system by transcription factors including Nrf1 and Nrf2 [ 70 , 71 , 72 ]. In a model of oculopharyngeal muscular dystrophy using Drosophila the increased activity of the ubiquitin-proteasome system conducts to muscle damage and impaired function [ 71 ]. The gene therapy to stimulate the production of inhibitors improved muscle weakness and reduced degeneration [ 71 ].…”

“…In a model of oculopharyngeal muscular dystrophy using Drosophila the increased activity of the ubiquitin-proteasome system conducts to muscle damage and impaired function [ 71 ]. The gene therapy to stimulate the production of inhibitors improved muscle weakness and reduced degeneration [ 71 ]. In other clinical conditions causing skeletal muscle atrophy, there was also increased activity of the ubiquitin-proteasome system and muscle protein degradation [ 72 ].…”