New study finds muscle stem cells are key to treating SMA
Low levels of SMN protein in muscle stem cells (MuSC) — specialized cells that help sustain muscle growth and regeneration — may contribute to the loss of motor neurons, the nerve cells that control movement and are progressively lost in spinal muscular atrophy (SMA), a new study in mice suggests.
According to the researchers, these findings indicate that these stem cells “may be important therapeutic targets for the long-term treatment of SMA.” Further, the team said, these results “provide important insights into the specific SMN requirements of MuSC, which could be valuable for … the development of next generation combinatorial therapies.”
The study, “Targeted knockdown of Smn in muscle stem cells induces non-cell autonomous loss of motor neurons,” was published in the journal Brain by a team of researchers in France.
SMA is chiefly caused by mutations in the SMN1 gene, which result in a deficiency of the SMN protein that’s essential for muscle health. The loss of this protein leads to SMA symptoms, including muscle weakness and wasting.
Skeletal muscles and MuSC are affected by this deficiency in the SMN protein. In undamaged muscle, MuSC remain quiescent, meaning they are not dividing into new cells. However, that is reversible, as they can be activated by a stimulus — a feature that is crucial for adult stem cell maintenance and tissue regeneration.
“While a direct contribution of muscle tissue in the disease progression has been demonstrated, the extent to which MuSC are involved in this process remains to be established,” the researchers wrote.
Investigating the role of SMN in muscle cell function
To learn more, the research team assessed the role of SMN in muscle stem cell function during early development and in adulthood in patient-derived muscle samples and in mouse models.
First, the team used muscle biopsies from people without neuromuscular disease and from untreated SMA type 2 patients, obtained during surgery to treat scoliosis — an abnormal sideways curvature of the spine that’s common in people with SMA.
“Importantly, these biopsies were harvested during scoliosis surgery, which implied that some of these muscles were likely to be chronically denervated,” or having lost nerve supply, the scientists wrote.
The results demonstrated that the mean number of quiescent MuSC containing the Pax7 protein marker in muscle fibers was significantly lower in SMA patients than in the control group. PAX7 is essential for the function of muscle stem cells.
Similar results were observed in a mouse model of severe SMA. Mice without SMN also had lower levels of quiescent MuSC and of muscle cells undergoing specialization, but higher levels of activated MuSC.
“We showed that SMN is an important regulator of [MuSCs] fate during early postnatal growth, and that SMN deficit compromises MuSC reservoir establishment,” the scientists wrote.
The early and sustained restoration of SMN in [muscle cells] would be an essential parameter to consider for next-generation therapeutic strategies.
In another mouse model in which part of the SMN gene is lacking in MuSC, the results showed reduced gene expression and lower SMN protein levels in adult muscle. Further tests showed increased apoptosis, a form of programmed cell death.
According to the researchers, these results demonstrate that “high levels of SMN are required for the maintenance of the quiescent MuSC reservoir.”
In addition, the depletion of the MuSC pool induced rapid alterations in the neuromuscular junction (NMJ), which is the region where nerve and muscle cells communicate to coordinate movement. This was evidenced by an increased proportion of polyinnervated NMJ, a hallmark of nerve injury in which a single muscle fiber receives input from several motor neurons.
In the long term, the reduction of the MuSC pool in adult muscle had a direct impact on motor neurons in the spinal cord, mediating a noncell autonomous loss of these cells. This means that the loss of motor neurons in the spinal cord was driven by damage to quiescent muscle stem cells, rather than to motor neurons themselves.
Based on these results, the researchers hypothesized that in SMA patients, inefficient restoration of SMN levels in muscle stem cells or starting treatment too late could lead to deterioration of the neuromuscular system in the long term.
Given these findings, the researchers concluded that “the early and sustained restoration of SMN in [muscle] progenitors would be an essential parameter to consider for next-generation therapeutic strategies.”
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