Oculopharyngeal Muscular Dystrophy as a Paradigm for Muscle Aging

Abstract

Symptoms in late-onset neuromuscular disorders initiate only from midlife onward and progress with age. These disorders are primarily determined by identified hereditable mutations, but their late-onset symptom manifestation is not fully understood. Here, we review recent research developments on the late-onset autosomal dominant oculopharyngeal muscular dystrophy (OPMD). OPMD is caused by an expansion mutation in the gene encoding for poly-adenylate RNA binding protein1 (PABPN1). The molecular pathogenesis for the disease is still poorly understood. Despite a ubiquitous expression of PABPN1, symptoms in OPMD are limited to skeletal muscles. We discuss recent studies showing that PABPN1 levels in skeletal muscles are lower compared with other tissues, and specifically in skeletal muscles, PABPN1 expression declines from midlife onward. In OPMD, aggregation of expanded PABPN1 causes an additional decline in the level of the functional protein, which is associated with severe muscle weakness in OPMD. Reduced PABNPN1 expression in muscle cell culture causes myogenic defects, suggesting that PABPN1 loss-of-function causes muscle weakness in OPMD and in the elderly. Molecular signatures of OPMD muscles are similar to those of normal muscle aging, although expression trends progress faster in OPMD. We discuss a working hypothesis that aging-associated factors trigger late-onset symptoms in OPMD, and contribute to accelerated muscle weakness in OPMD. We focus on the pharyngeal and eyelid muscles, which are often affected in OPMD patients. We suggest that muscle weakness in OPMD is a paradigm for muscle aging.

Inhibition of myostatin improves muscle atrophy in oculopharyngeal muscular dystrophy (OPMD)

“…The aggregates sequester wild‐type PABPN1 among other essential components of the cell, thereby dysregulating essential functions of the cell . Interestingly, it has been shown that PABPN1 expression in muscles declines with age in healthy individuals, with OPMD patients presenting molecular signatures of premature ageing . Global approaches have generated a body of evidence—including mitochondrial defects, altered RNA metabolism, specific oxidative fibre atrophy, and increased proteasome activity—suggesting a premature ageing in OPMD muscles.…”

“…[12][13][14][15][16][17][18][19][20] Interestingly, it has been shown that PABPN1 expression in muscles declines with age in healthy individuals, with OPMD patients presenting molecular signatures of premature ageing. 12,21 Global approaches have generated a body of evidence-including mitochondrial defects, altered RNA metabolism, specific oxidative fibre atrophy, and increased proteasome activity-suggesting a premature ageing in OPMD muscles. This has also been implicated in the comparison of the molecular signature of OPMD patients and models of muscle ageing.…”

Aging‐associated genes and let‐7 microRNAs: a contribution to myogenic program dysregulation in oculopharyngeal muscular dystrophy

“…Although OPMD is usually classified as a muscular dystrophy, the analysis of the RNA expression profiles in OPMD patient muscles and cellular and animal models revealed higher similarities with muscles of the healthy elderly rather than with those with muscular dystrophy or myopathy (11), suggesting common molecular signatures with aged muscles. In view of these considerations, OPMD should be regarded as a disorder of accelerated muscle aging (11).…”

“…OPMD is caused by short (GCN) trinucleotide expansion in the coding sequence of PABPN1, which leads to an expanded polyalanine tract at the N terminus of the protein (10). Accumulation of expanded PABPN1 into insoluble intranuclear inclusions in skeletal muscle fibers is considered the pathologic hallmark of OPMD (11). PABPN1 is a ubiquitous nuclear protein that binds with high affinity to polyadenosine RNA, and it is involved in mRNA polyadenylation (12) other than in the regulation of mRNA decay.…”

Reduced PABPN1 levels causes cytoskeleton disorganization and aberrant differentiation

“…An expansion mutation in PABPN1 is the genetic cause for oculopharyngeal muscular dystrophy (OPMD), a late onset myopathy (reviewed in: Brais, 2009). In OPMD, reduced levels of functional PABPN1 are caused by both aggregation of the expanded PABPN1 and reduced PABPN1 mRNA levels (Raz & Raz, 2014). Reduced PABPN1 levels (named shPab in mouse and shPAB in human) cause muscle wasting and atrophy (Olie et al, 2019, Riaz et al, 2016.…”