Toxic protein assemblies, or "amyloids", gum up a cell. Credit: iStock
Toxic protein assemblies, or 鈥渁myloids,鈥� 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.
鈥淥urs 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,鈥� said co-first author Thomas Vogler, an M.D./PhD candidate in the Department of Molecular, Cellular, and Developmental Biology (MCDB).听
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.
Josh Wheeler, left, and Tom Vogler celebrate on the summit of Longs Peak. The friends, competitive runners, and M.D., PhD candidates published a paper this week that sheds new light on how neuromuscular diseases like ALS may originate.
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鈥檚 and Alzheimer鈥檚 disease, in which different amyloids play a role.
鈥淢any 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,鈥� said co-first author Joshua Wheeler, also an M.D./PhD candidate in the Department of Biochemistry. 鈥淥ur data suggest that the cell is just damaged and trying to repair itself.鈥�
Wheeler and Vogler, both competitive runners and participants in CU鈥檚 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鈥檚 lab. Wheeler studies protein assemblies in Biochemistry Professor Roy Parker鈥檚 lab. In pursuit of their medical degrees, both frequently see patients with neuromuscular disorders believed to be driven by amyloids.
鈥淓ach of our different fields were kind of on a collision course for each other,鈥� 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. 听
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.
鈥淭hat was astounding,鈥� said Olwin. 鈥淭hese 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.鈥�
- Amyloids, or toxic protein assemblies, are often found in cells and neurons of people with neurodegenerative听diseases and were believed to be toxic.
- A new paper in听狈补迟耻谤别听shows they are also present in healthy muscle tissue as it regenerates and likely key to its formation.
- The research could lead to new treatment avenues for ALS, neurodegenerative diseases听and age-related muscle wasting.
Subsequent studies in muscle tissue growing in culture showed that when the gene that codes for TDP-43 was knocked out, muscles didn鈥檛 grow. When the researchers looked at human tissue biopsied from healthy people whose muscles were regenerating, they found aggregates, or 鈥渕yo-granules,鈥� of TDP-43.听
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 鈥� like sugar cubes that won鈥檛 dissolve 鈥� cluster together and cause disease?
鈥淚f they normally form and go away, something is making them dissolve,鈥� said Olwin. 鈥淔iguring out the mechanisms involved could potentially open a new avenue for treatments.鈥�
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.
鈥淭his is a great example of how collaboration across disciplines can lead to really important work,鈥� said Parker.
Someday, Wheeler and Vogler are hopeful the work they do in the lab will help the patients they see in the clinic.
鈥淭he 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,鈥� said Wheeler. 鈥淲e are just opening the door on this.鈥�
Researchers from Johns Hopkins University School of Medicine, the University of California Los Angeles, St. Jude Children鈥檚 Research Hospital, Perleman School of Medicine at University of Pennsylvania, and Howard Hughes Medical Institute also contributed to this study.
