International Business Department           Liu Bojia           August 07, 2024

  At the Olympic Games, the sporting event where mankind demonstrates faster, higher and stronger, athletes can be admired for putting their muscles to the test, whether it's an event that's won with speed or one that's won with strength or confrontation.

  Muscle force is generated through the contraction of muscle fibres, which requires motor neurons to control the skeletal muscles. For humans, the ability to control the contraction of skeletal muscles does not come with birth. Humans have poor muscle coordination in the first few months of life, and it usually takes about a year for infants to develop a set of muscles for coordinated walking. Many other mammals are much better at this than humans, such as horses or cows, which can stand up on the day of birth and walk or even run before long.

  Why do cows and horses stand at birth, while humans take so long to "unlock" muscle control? Researchers at the University of California, San Diego (UCSD) have inadvertently unravelled the mystery through structural biology. Their findings, which were recently published in the leading academic journal Nature, also provide ideas for future treatments for adult muscle weakness.

  The key to understanding how a muscle initiates a contraction lies in the "neuromuscular junction" (NMJ), the point at which a motor neuron connects to a skeletal muscle fibre. Scientists have been studying the workings of the NMJ for more than a century and have determined that acetylcholine (ACh) molecules released from the endings of motor neurons act like a key to unlock the acetylcholine receptor (AChR) on the muscle cells of skeletal muscle, which initiates a strong contraction of the muscle fibre.

  In the new study, scientists used cutting-edge cryo-electron microscopy (cryo-EM) techniques to obtain high-resolution three-dimensional structures of the muscle AChR at a resolution of 2.5 Å when it is bound or unbound to ACh, respectively, which, according to a press release from the UCSD, are the first three-dimensional structural maps of the muscle AChR.

  The challenge of this work came firstly from the acquisition of samples. The paper describes that despite the high density of AChR in mature skeletal muscle, the weight percentage of AChR in skeletal muscle is extremely low, and it would be difficult to obtain enough tissue samples to isolate AChR from human muscle. So the researchers thought of the much more readily available beef and turned to muscle from bovine embryos, ultimately obtaining 30 micrograms of purified AChR from each kilogram of beef. in addition, the researchers cleverly substituted cobra venom for acetylcholine in binding to the AchR, in order to see the conformational changes that occur to the AChR after recognising the signalling molecule.

  And when the researchers obtained high-definition three-dimensional structural maps of the muscle AChR, they discovered, to their surprise, that two versions of the AchR could be seen simultaneously from the same sample of embryonic tissue: an immature embryonic version, and a version in a mature neuromuscular junction. Both versions of the AChR consist of five subunits arranged in a ring, forming a cation-selective ion channel, but the subunit composition is not identical.

  Normally, the AChR needs to complete a subunit transition as the neuromuscular junction matures, but the structural principles of how the transition from the embryonic to the mature type occurs are not clear.

  And now, researchers are simultaneously seeing two versions of the AChR right in the muscle tissue of the early bovine embryo, one AChR allowing nerve endings to form connections with the muscle, and the other controlling muscle contraction. With high-resolution 3D structural maps, it is now possible to correlate the structural differences between the two muscle AchRs with their functional differences, such as changes in the acetylcholine binding site and the effect of subunit interactions on the duration of channel opening.

  Meanwhile, the previous query has just been answered: why do animals like cows walk on the day of birth? Looking at their muscles, it turns out that cattle complete the developmental transition of AChR subunit composition long before birth, forming a mature neuromuscular junction.

  And based on new discoveries about the structure of muscle AChR, researchers hope to next provide insight into understanding and treating myasthenia gravis. This is because the root cause of myasthenia gravis is the destruction of the muscle AChR, which results in the inability of the patient to effectively control the contraction of the skeletal muscle to generate force.