Loss of TRIO Expression at Neuromuscular Junctions Precedes Age-Related Loss of Motor Function

Many mechanisms are thought to contribute to the age-related decline of muscle mass and strength, but there are the usual debates over which are more important, which are the primary causes, and how they relate to one another. Little of our biochemistry is as fully understood as we might like it to be, and in some senses even the very well understood regions are only sketches of a yet to be fully mapped environment. One hypothesis places degeneration of neuromuscular junctions as an early cause, leading to the other observed issues. A neuromuscular junction is the synaptic connection between a motor neuron and muscle fiber, allowing the muscle to contract. The degree to which muscles are innervated in this way appears to go a long way towards determining how well they are maintained and function.

Unfortunately, and like all complex small scale structures in the body, neuromuscular junctions are subject to the damage and disarray of aging. The expression of necessary genes changes, the surrounding signaling environment changes, nearby cell behavior changes. All of this is disruptive, leading to loss of neuromuscular junctions and a reduced ability to function where they remain more or less intact. Like all aspects of aging, researchers have yet to build a complete understanding of how exactly the identified low-level processes of aging give rise to these high-level manifestations. They have also yet to produce a complete map of the important alterations in the expression of genes in aging neuromuscular junctions, and the consequences of those alterations - but more attention is given to that layer of degenerative aging, for better or worse.

Trio preserves motor synapses and prolongs motor ability during aging

Across species, motor ability diminishes as aging progresses, and this curtailment is one of the most debilitating aspects of human aging. Concomitant with the age-dependent decline of motor ability are degenerative alterations of motor synaptic structures. These changes include the subdivision or fragmentation of neuromuscular junction (NMJ) synaptic terminals into smaller units in addition to a reduction in the size or number of terminals. These structural alterations are associated with a decline of neurotransmitter release, which may undermine motor ability during aging.

We have shown previously that Drosophila neuromuscular synapses undergo structural synaptic bouton fragmentation during aging, co-incident with the decline of motor ability. Here, investigating mechanisms that could contribute to age-dependent synaptic structural degeneration, we find that levels of Trio, an evolutionarily conserved guanine nucleotide exchange factor (GEF), decline at NMJ synapses with age. We discover that increasing Trio levels during aging has a remarkable ability to conserve synaptic structures and prevent bouton fragmentation, maintaining the capacity of synapses to sustain high intensities of neurotransmitter release and enabling a postponement of the age-dependent decline of motor ability. Enhanced Trio expression can also prevent accelerated synaptic structural degeneration induced by loss of miniature neurotransmission.

Our results support a paradigm where the structural dissolution of motor synapses precedes and promotes motor behavioral diminishment and where intervening in this process can postpone the decline of motor function during aging.

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