A developmental process responsible for fine-tuning nervous system connections to muscle fibers may inappropriately reactivate in later life, becoming an important contributing cause of the characteristic loss of muscle strength and control that occurs in aging:
Proteins in the family MHCI, or major histocompatibility complex class I, "prune" the connections, or synapses, between motor neurons and muscle fibers. Pruning is necessary during early development because at birth each muscle fiber in humans, mice and other vertebrates receives signals from dozens of neural connections. Proper motor control, however, requires that each muscle fiber receive signals from only a single motor neuron, so without the pruning carried out by MHCI proteins, fine motor control would never emerge. It is not known why more synapses are made during development than are needed. One possibility is that it allows the wiring diagram of the nervous system to be precisely tuned based on the way the circuit is used. MHCI proteins help limit the final number of connections so that communication between neurons and muscles is more precise and efficient than would be possible using just a molecular code that produced a set number of connections.
Researchers also found that MHCI levels can rise again in old age, and that the proteins may resume pruning nerve-muscle synapses - except that in a mature organism there are no extra synapses. The result is that individual muscle fibers become completely "denervated," or detached from nervous system control. Denervated muscle fibers cannot be recruited during muscle contraction, which can leave older people weaker and more susceptible to devastating falls, making independent living difficult. However, the researchers discovered that when MHCI levels were reduced in mice, denervation during aging was largely prevented. The mice actually lacked a protein known as beta-2 microglobulin, which forms a complex with MHCI and is necessary for MHCI expression on the surface of cells. This could be beneficial from a clinical perspective because beta-2 microglobulin is a soluble protein and can be removed from the blood. "Our studies raise the possibility that targeting one protein could help with both motor and cognitive aspects of aging." Because MHCI proteins are important in the immune system, however, such an approach could result in compromised immunity. Future work will include exploring the effectiveness of other approaches to reducing the proteins' synapse-eliminating activity in older nervous systems, ideally while leaving their immune functions intact.