Insights into muscle degeneration from heritable inclusion body myopathies.

Sabine Krause

doi:10.3389/fnagi.2015.00013

Abstract

Muscle mass and function are gradually lost in age-related, degenerative neuromuscular disorders, which also reflect the clinical hallmarks of sarcopenia. The consensus definition of sarcopenia includes a condition of age-related loss of muscle mass, quality, and strength. The most common acquired muscle disease affecting adults aged over 50 years is sporadic inclusion body myositis (sIBM). Besides inflammatory effects and immune-mediated muscle injury, degenerative myofiber changes are characteristic features of the disease. Although the earliest triggering events in sIBM remain elusive, a plethora of downstream mechanisms are implicated in the pathophysiology of muscle wasting. Although it remains controversial whether hereditary forms of inclusion body myopathy (IBM) may be considered as degenerative sIBM disease models, partial pathophysiological aspects can mimic the much more frequent sporadic condition, in particular the occurrence of inclusion bodies in skeletal muscle. Various clinical aspects in genetically determined skeletal muscle disorders reflect age-related alterations observed in sarcopenia. Several intriguing clues from monogenic defects in heritable IBMs contributing to the molecular basis of muscle loss will be discussed with special emphasis on inclusion body myopathy with Paget’s disease of bone and frontotemporal dementia (IBMPFD) and GNE myopathy. Finally, also the recently identified dominant multisystem proteinopathy will be considered, which may rarely present as IBM.

Highlights

Pathogenic mutations in genes involved in diverse cellular pathways as VCP/p97, called valosin-containing protein [resulting in autosomal-dominant inclusion body myopathy (IBM) associated with Paget’s disease of bone and frontotemporal dementia, IBMPFD] and GNE, referred to as UDP-N -acetyl-dglucosamine 2-epimerase/N -acetylmannosamine kinase (GNE) can elicit a pathophysiological phenotype in skeletal muscle that partially overlaps with histopathology findings in sporadic inclusion body myositis, in particular the detection of inclusion bodies in skeletal muscle
Our findings further extend the functional spectrum of VCP/p97 and suggest an additional molecular pathomechanism for IBMPFD at the level of chromatin remodeling and transcription control (Bonizec et al, 2015)
In conclusion, it will be essential to continue studying fundamental cellular pathways underlying muscular hypertrophy and atrophy to advance the discovery of promising targets for the development of causative and safe therapies for skeletal muscle disorders

Summary

Sabine Krause*

Muscle mass and function are gradually lost in age-related, degenerative neuromuscular disorders, which reflect the clinical hallmarks of sarcopenia. The earliest triggering events in sIBM remain elusive, a plethora of downstream mechanisms are implicated in the pathophysiology of muscle wasting. It remains controversial whether hereditary forms of inclusion body myopathy (IBM) may be considered as degenerative sIBM disease models, partial pathophysiological aspects can mimic the much more frequent sporadic condition, in particular the occurrence of inclusion bodies in skeletal muscle. Various clinical aspects in genetically determined skeletal muscle disorders reflect age-related alterations observed in sarcopenia. The recently identified dominant multisystem proteinopathy will be considered, which may rarely present as IBM

INTRODUCTION

Findings

CONCLUSION