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Muscles are constantly exposed to mechanical stress, which can lead to damage and degeneration, especially in conditions such as muscle atrophy and other muscle-related diseases. In a study published on August 11, 2024 in Nature Communications, a team led by Professor Thorsten Hoppe from the CECAD Cluster of Excellence for Aging Research at the University of Cologne identified the E3 ligase NHL-1 as a key regulator of the muscle motor protein myosin during mechanical stress. This research, part of the Research Unit FOR 2743 on Mechanical Stress Protection, involved extensive collaboration with researchers in Cologne and Warsaw.
PhD student Carl Elias Kutzner has developed a new model using the nematode Caenorhabditis elegans to study how muscles respond to stress. The model uses optogenetics, a light-activated switch that uses blue light to control muscle contractions in the 1-mm worm C. elegans, mimicking real muscle damage. Using proximity proteomics, the researchers mapped the interactions between the muscle motor protein myosin, its chaperone UNC-45, and NHL-1. They discovered that while UNC-45 repairs damaged myosin, NHL-1 targets irreparably damaged proteins for degradation, acting as a cellular waste disposal system that protects muscle function under stress.
In muscle, myosins are sophisticated motor proteins that generate force and enable contraction and movement. Myosins are assembled by a specialized engineering protein called the chaperone UNC-45. Intense contraction and exertion of the muscle causes damage to the motor, which must be either repaired or replaced. This research shows that these motors are either repaired by the chaperone UNC-45 or handed off to a special disposal protein called NHL-1 for removal.
"This new experimental setup allowed us to induce mechanical stress in muscle cells by exposing them to blue light and to monitor repair and degradation processes in real time," said Prof. Thorsten Hoppe. "Our findings on the regulation of muscle motor proteins mark a crucial step in understanding cellular responses to mechanical stress and open new avenues for the development of treatments for muscle injury, disease and age-related muscle wasting."
The experimental work, conducted by PhD students Carl Elias Kutzner and Karen Carolyn Bauer, was supported by Jan-Wilm Lackmann, Richard James Acton, and the CECAD Proteomics, Imaging, and Bioinformatics Facilities, as well as Dr. Wojciech Pokrzywa’s team at the International Institute of Molecular and Cell Biology (IIMCB) in Warsaw, Poland. This study is part of FOR 2743’s broader effort to understand how different cell types, including those in muscles, skin, and kidneys, respond to mechanical stress. The collaboration, spanning six years, has produced key insights that could lead to new therapies for muscle recovery and combat degeneration associated with aging and disease.
Media Contact:
Professor Dr. Thorsten Hoppe
CECAD Cluster of Excellence for Aging Research
+49 221 478 84218
thorsten.hoppe[at]uni-koeln.de
Press and Communications Team:
Dr. Tanio Calabrese
+49 221 478 84044
g.calabrese[at]uni-koeln.de
Publication:
https://www.nature.com/articles/s41467-024-51069-3
Further information: