Poor muscle signaling may drive bone loss in SMA, study shows

Weak bones in people with spinal muscular atrophy (SMA) may be driven by disrupted muscle-to-bone communication, a study in China showed.

The researchers suggested that low levels of SMN protein — a hallmark of SMA — drive low levels of another protein, SNAP23, which in turn impairs the release of tiny sacs that regulate muscle-bone communication. In the mouse studies, restoring SNAP23 improved bone formation, increased bone density, and reduced bone loss.

The scientists said the study “highlights the therapeutic potential of replenishing SMA-[vesicles] … offering a promising strategy to improve skeletal health in SMA.”

The study, “SMN deficiency contributes to osteoporosis in spinal muscular atrophy by impairing Snap23 meditated muscle-derived extracellular vesicle secretion,” was published in the Journal of Translational Medicine.

Recommended Reading

June 9, 2026 Columns by Connie Chandler

3 exercises I can do from my wheelchair, and why I do them

Communication regulators tied to bone health

SMA is caused mainly by mutations in the SMN1 gene that result in reduced SMN protein levels. This leads to the progressive loss of motor neurons (specialized nerve cells responsible for movement control) and symptoms such as muscle weakness and wasting.

Poor bone health and osteoporosis, a condition marked by weak, brittle bones, are common in SMA. Extracellular vesicles (EVs) released by muscle cells have emerged as regulators of muscle-bone communication and are thought to play a role in the natural processes that drive bone health. “Whether muscle derived EVs of SMA … are involved in the disrupted bone metabolism of SMA, however, is unknown,” the scientists wrote.

Using imaging techniques and muscle and bone samples, the researchers found SMA patients had significantly lower bone density in the spinal cord and severe muscle loss. Similar findings were seen in a mouse model of SMA.

Further analyses demonstrated that while EVs produced by SMA patients’ muscles appeared normal in size and structure, the number of vesicles and their protein content were significantly reduced in people with SMA. The same was observed in mice.

When SMA-derived vesicles were labeled with a fluorescent dye and injected into mice, they were detected in several tissues, including the bone marrow, within one hour. SMA EVs were taken up by bone marrow cells involved in bone healing and formation, called bone marrow mesenchymal stem cells (BMSCs) and bone marrow-derived macrophages (BMMs). BMSCs are the precursors of osteoblasts, bone-building cells, and BMMs are precursors of osteoclasts, cells responsible for bone resorption.

“These results demonstrate that SMA-EVs can systemically reach the bone marrow niche and be taken up by key cellular regulators of bone homeostasis,” the researchers wrote.

Additional experiments showed that SMA EVs stimulated BMSCs to produce proteins associated with bone growth and suppressed BMMs from producing proteins associated with bone resorption. Again, the same pattern was seen in mice.

These benefits were dose-dependent, meaning stronger effects occurred with higher EV amounts. When given in sufficient amounts, SMA EVs were nearly as effective as EVs from healthy muscle. “These data suggest that the primary defect in SMA is a reduction in muscle-derived EVs quantity rather than a severe qualitative impairment of their bone-modulating cargo,” the investigators wrote.

Restoring muscle-derived EVs in SMA mice increased bone formation and improved key bone structure measures after three weeks. “This confirms that the deficit in muscle EVs is a major contributor to osteoporosis in SMA and that its replenishment is therapeutically viable,” the researchers wrote.

Using muscle samples from patients, the team found less activity in genes coding for proteins of the SNARE family, which mediate EVs’ transport and release from cells. One of them, SNAP23, stood out as its role in EV release from cells outside the nervous system has been established.

When the researchers restored SNAP23 levels in SMA muscle, EV production returned to near-normal levels, and bone loss was eased. Experiments in mice also revealed that having more SMN protein in muscle was associated with more SNAP23 and more EV release.

“These data establish SNAP23 as a crucial downstream effector impaired in SMA muscle, responsible for the EV secretion defect,” the researchers wrote. “Mechanistically, we linked SMN deficiency to defective EV secretion, revealing for the first time in a non-neuronal tissue (skeletal muscle) that SMN is a key regulator of … vesicle secretion.”

“This mechanistic discovery has straightforward translational value,” they wrote. “Current disease-modifying therapies for SMA … primarily aim to increase SMN levels in the central nervous system to rescue motor neurons. Our research indicates that increasing SMN (or its downstream effector SNAP23) in muscle tissue is equally crucial, holding promise for concurrently ameliorating osteoporosis.”