New Potential SMA Therapeutic Target Found in Muscle Cells, Mouse Study Suggests
Deficits in the secretion of a protein called CTRP3 by muscle cells contribute to the significantly lower survival motor neuron (SMN) protein levels observed in spinal muscular atrophy (SMA), a mouse study suggests.
These findings indicate that restoring CTRP3 levels in people with SMA could potentially increase SMN levels in motor neurons and slow disease progression.
The study, “Muscle regulates mTOR dependent axonal local translation in motor neurons via CTRP3 secretion: implications for a neuromuscular disorder, spinal muscular atrophy,” was published in the journal Acta Neuropathologica Communications.
The SMN protein, which is lacking in people with SMA, is critical for the growth, protein synthesis, and survival of motor neurons — the nerve cells responsible for controlling voluntary muscles — and their communication with muscle cells.
While SMA is mainly considered a motor neuron disease, recent studies have suggested that SMN deficiency causes damage in muscle cells that occur before motor neuron degeneration.
“However, whether or how defects in muscles influence motor neuron [functioning], and whether this contributes to SMA [development] is utterly unknown,” the researchers wrote in the study.
These researchers in Germany and the U.S. set out to evaluate the potential influence of muscle cells in motor neurons in the context of SMA.
By analyzing differences in secreted proteins between healthy and SMA muscle cells, they found that the levels of the CTRP3 protein were significantly lower in SMA muscle cells.
CTRP3, a protein that circulates in the blood, is known to be involved in cell growth and survival and to be present in the cerebrospinal fluid (the liquid surrounding the brain and spinal cord).
An SMA mouse model also showed significantly lower levels of CTRP3 in a leg muscle (reported to be particularly vulnerable in these mice), in the blood and in the brain, compared with healthy mice.
Further analysis on the potential role of muscle-secreted CTRP3 showed that CTRP3 boosts protein production — including of SMN and VEGF — in motor neurons isolated from healthy and SMA mice. However, the increase in SMN production was slower in SMA motor neurons than in healthy ones.
VEGF is a molecule involved in blood vessel formation and known to be regulated by CTRP3 in the brain.
Results also revealed that CTRP3 boosted protein synthesis in both the cell body and axons of SMA motor neurons. Axons are the elongated, thread-like projections of neurons that conduct impulses and allow communication with other cells, including muscle cells.
However, protein production in axons appeared to be particularly impaired, compared with that in the cell body, which the researchers noted is in agreement with previous reports showing protein synthesis deficits in axons of SMA neurons.
The team also found that CTRP3 increased protein production in SMA motor neurons through mTOR, a major pathway involved in protein synthesis in neurons.
“This is the first report showing that muscle regulates neuronal protein synthesis via the secretory pathway and that this process is dysregulated in the genetic neuromuscular disease, SMA,” the researchers wrote.
“We can speculate that restoring CTRP3 levels in SMA would increase the levels of SMN and VEGF, and thereby attenuate SMA disease progression,” they added.