Amyloid assemblies once believed to be toxic found to play key role in muscle generation

Amyloid assemblies once believed to be toxic found to play key role in muscle generation


Toxic protein assemblies, or "amyloids," long considered to be key drivers in many neuromuscular diseases, also play a beneficial role in the development of healthy muscle tissue, researchers have found.

"Ours is the first study to show that amyloid-like structures not only exist in healthy skeletal muscle during regeneration, but are likely important for its formation," said co-first author.

The surprising finding, published in the journal Nature, sheds new light on the potential origins of a host of incurable disorders, ranging from amyotrophic lateral sclerosis (ALS) to inclusion body myopathy (which causes debilitating muscle degeneration) to certain forms of muscular dystrophy.

The researchers believe it could ultimately open new avenues for treating musculoskeletal diseases and also lend new understanding to related neurological disorders like Parkinson's and Alzheimer's disease, in which different amyloids play a role.

"Many of these degenerative diseases share a similar scenario in which they have these protein aggregates that accumulate in the cell and gum up the system," said another co-first author. "As these aggregates are beneficial for normal regeneration, our data suggest that the cell is just damaged and trying to repair itself."

TDP-43 has long been suspected to be a culprit in disease, having been found in the skeletal muscle of people with inclusion body myopathy and the neurons of people with ALS. But when the researchers closely examined muscle tissue growing in culture in the lab, they discovered clumps of TDP-43 were present not only in diseased tissue but also in healthy tissue.

"That was astounding," said the author. "These amyloid-like aggregates, which we thought were toxic, seemed to be a normal part of muscle formation, appearing at a certain time and then disappearing again once the muscle was formed."

Subsequent studies in muscle tissue growing in culture showed that when the gene that codes for TDP-43 was knocked out, muscles didn't grow. When the researchers looked at human tissue biopsied from healthy people whose muscles were regenerating, they found aggregates, or "myo-granules," of TDP-43. Further RNA-protein mapping analysis showed that the clusters - like shipping trucks traveling throughout the cell - appear to carry instructions for how to build contractile muscle fibers.

The data suggest that when healthy athletes push their muscles hard via things like marathons and ultramarathons, they are probably also forming amyloid-like clusters within their cells.

The key question remains: Why do most people quickly clear these proteins while others do not, with. the granules - like sugar cubes that won't dissolve - clustering together and causing disease?

"If they normally form and go away, something is making them dissolve," said the author. "Figuring out the mechanisms involved could potentially open a new avenue for treatments."

The team is also interested in exploring whether a similar process may occur in the brain after injury, kick-starting disease. And subsequent studies will go even further to identify what the protein clusters do.

https://www.nature.com/articles/s41586-018-0665-2

Edited

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