Using advanced visualization technologies, scientists have successfully obtained the first 3-D images of an essential muscle receptor, revealing important information on muscle development in various animals and opening up possibilities for future treatments for muscular disorders.
The way muscles connect with the nervous system varies significantly throughout the animal kingdom. For instance, while human infants take about a year to develop the muscular strength needed for walking, calves can stand and run within minutes of being born.
Researchers at the University of California San Diego have used these cutting-edge visualization techniques to understand the distinct differences in muscle development between species. Their findings shed light on how muscle contractions work in humans, potentially leading to new therapies for muscle-related diseases.
“Our goal in this research was to delve into the molecular details of muscle contraction at the junction where motor neurons meet skeletal muscles, which are the muscles we can control,” explained Professor Ryan Hibbs, who is part of the School of Biological Sciences. This study has been published in Nature. “We identified changes in the composition of muscle proteins during their development, which is relevant for conditions that result in progressive muscle weakness.”
Skeletal muscles allow our bodies to perform various actions—such as walking, jumping, breathing, and blinking—by contracting. These contractions begin at the junction between motor neurons, which emerge from the spinal cord and brainstem, and muscle fibers. At this junction, neurons release a chemical messenger called acetylcholine. This neurotransmitter attaches to protein receptors on muscle cells, prompting the cell membrane to open and allowing electrical currents to enter, which leads to the contraction of the muscles.
For over a century, scientists have used this chemical communication between neurons and muscles as a model for study. However, one crucial aspect that was previously lacking was a visual representation of how this mechanism operates. What does the structure of the receptor protein responsible for muscle contraction look like?
To answer this question, Hibbs, along with postdoctoral researcher Huanhuan Li and research data analyst Jinfeng Teng, utilized cryo-electron microscopy (cryo-EM) available at UC San Diego’s groundbreaking Goeddel Family Technology Sandbox, a center for advanced research tools. Cryo-EM employs extremely powerful microscopes to capture images of molecules that are “frozen” in their positions.
The resulting images provided the first 3-D visualizations of the muscle acetylcholine receptor. Since it’s challenging to obtain human tissue for such studies, the team worked with fetal cow skeletal muscle samples. To isolate the receptor from these samples, the researchers used an unexpected source: snake venom. A neurotoxin from a venomous snake was employed to bind to the muscle receptors in cow tissue, facilitating the researchers’ ability to extract and study these receptors. The cryo-EM images then allowed them to observe the receptor’s developmental process.
Alongside this new data, the researchers stumbled upon an additional discovery—they were able to view both fetal and adult versions of the receptors from the same fetal cow tissue samples.
“While we aimed to visualize the receptor structure, we were also surprised to find two distinct forms of it,” said Hibbs. “That was unexpected.”
In hindsight, discovering these two receptor types makes sense, according to Hibbs. As calves grow inside the womb, the presence of fetal receptors was anticipated. To be able to walk shortly after birth, they begin developing adult nerve-muscle connections much earlier in their growth.
“This finding clarifies how animals like cows, which must walk soon after birth, create mature neuromuscular junctions before they are born, unlike humans, who face coordination challenges for several months after birth,” noted Hibbs. “By examining the intricate details of these receptors, we can link their differences to how one facilitates nerve-muscle connections while the other enables muscle contractions.”
The insights gained from this research are already being utilized to explore muscle-related conditions, such as congenital myasthenic syndromes (CMS), which lead to muscle weakness. A well-known autoimmune disorder called myasthenia gravis occurs when antibodies mistakenly attack the muscle acetylcholine receptor, resulting in weakened skeletal muscles.
“This in-depth understanding of the muscle receptor will aid researchers in comprehending how gene mutations lead to disease, and could pave the way for personalized treatment options for patients with various conditions in the future,” stated lead author Li.
