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, CU Boulder 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 Thomas Vogler, an M.D./PhD candidate in the Department of Molecular, Cellular, and Developmental Biology (MCDB).
The surprising finding, published today 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 authors believe the findings could ultimately open new avenues for treating musculoskeletal diseases and age-related muscle decline. They could also lend new understanding to 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 co-first author Joshua Wheeler, also an M.D./PhD candidate in the Department of Biochemistry. “Our data suggest that the cell is just damaged and trying to repair itself.”
Wheeler and Vogler, both competitive runners and participants in CU’s Medical Science Training Program, came up with the idea for the study while on a trail run in the hills West of Boulder.
Vogler studies muscle generation in MCDB Professor Brad Olwin’s lab. Wheeler studies protein assemblies in Biochemistry Professor Roy Parker’s lab. In pursuit of their medical degrees, both frequently see patients with neuromuscular disorders believed to be driven by amyloids.
“Each of our different fields were kind of on a collision course for each other,” says Wheeler.
That collision turned into a collaboration in which their two labs, and colleagues at Anschutz Medical Campus, set out to study a specific protein called TDP-43. 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 surprisingly, 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 Olwin. “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.
Wheeler, a competitive ultrarunner, says the data suggest that when healthy athletes push their muscles hard, via events like marathons or 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 in others the granules – like sugar cubes that won’t dissolve – cluster together and cause disease?
“If they normally form and go away, something is making them dissolve,” said Olwin. “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. More research is already underway.
“This is a great example of how collaboration across disciplines can lead to really important work,” said Parker.
Someday, Wheeler and Vogler are hopeful the work they do in the lab will help the patients they see in the clinic.
“The holy grail of all this is to be able to treat devastating and incurable diseases like ALS and to develop therapeutic strategies to improve skeletal muscle and fitness,” said Wheeler. “We are just opening the door on this.”
Researchers from Johns Hopkins University School of Medicine, the University of California Los Angeles, St. Jude Children’s Research Hospital, Perleman School of Medicine at University of Pennsylvania, and Howard Hughes Medical Institute also contributed to this study.