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How Muscles Keep Fit: Molecular Machinery Unlocked

Illustration: Functioning of the machinery degrading misfolded intermediate filaments due to genetic diseases. The recognition and degradation of misfolded intermediate filament polymers prior to the formation of toxic aggregates is controlled by a protein complex (MTM1-UBQLN2 and chaperones).  This machinery is deregulated in myotubular myopathy (also known as X-linked centronuclear - XLCNM) and certain myofibrillary myopathies (MFM).      

The MTM1-UBQLN2-HSP complex mediates degradation of misfolded intermediate filaments in skeletal muscle.

Gavriilidis C(1)(2)(3)(4), Laredj L(1)(2)(3)(4), Solinhac R(5), Messaddeq N(2)(3)(4), Viaud J(5), Laporte J(1)(2)(3)(4), Sumara I(2)(3)(4)(6), Hnia K(7)(8)(9)(10)(11).

Nat Cell Biol Feb 2018

Feb. 15, 2018

Several rare myopathies are caused by alterations of proteins involved in muscle cell structure. These cause non-degraded toxic aggregates in the muscle. An earlier study by Dr. Jocelyn Laporte's team at IGBMC revealed an interaction between desmin, an intermediate filament of the cell cytoskeleton, and myotubularin (MTM1) in the dysfunctional degradation process related to two myopathies. In this new study recently published in Nature Cell Biology and conducted in synergy with Dr. Isabela Sumara's team at IGBMC, the degradation mechanism of defective intermediate filaments is revealed, opening up new therapeutic research perspectives. 

The accumulation of aberrant proteins in the striated muscle is a characteristic of a group of genetic pathologies called proteinopathies. More particulary, myofibrillary myopathies are due to alterations in the proteins of the muscular contractile apparatus such as the intermediate filaments of desmin. An accumulation of polymers of misfolded desmin causes the progressive formation of toxic protein aggregates leading to skeletal muscle atrophy.

The mechanism used by the muscle cell to degrade these misfolded proteins is still not well known. Dr Jocelyn Laporte’s team in collaboration with Dr Izabela Sumara’s team, both from IGBMC, has demonstrated a molecular mechanism used by the skeletal muscle to detect and degrade these aberrant proteins. This process involves a protein complex containing myotubularin (MTM1), a protein whose deficiency causes a severe myopathy called myotubular myopathy, and another protein called ubiquilin-2 (UBQLN2) involved in protein recognition and degradation.

The discovery of this mechanism opens up a new field of investigation: exploring these molecular machines in other proteinopathies could indeed allow to identify more specific therapeutic targets in these pathologies. This project, developed under the supervision of Dr. Hnia, in Dr Jocelyn Laporte’s team, was completed at the Institute of Metabolic and Cardiovascular Diseases in Toulouse (I2MC, INSERM-UMR-1048).


This study was in part-financed by AFM (Association Française contre les Myopathies) and ANR (Agence Nationale pour la Recherche), IDEX and LABEX INRT.

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