Metabolism drugs may hold promise for SMA, mouse study shows

Treatment with melatonin and pioglitazone, two approved drugs that act on metabolism, improved motor function and prolonged survival in a mouse model of spinal muscular atrophy (SMA), with melatonin having the greater impact on survival, a study showed.

The findings provide “strong rationale for exploring metabolism-targeted second-generation therapies to complement currently approved disease-modifying treatments,” the researchers wrote.

The study, “Treating Smn2B/− spinal muscular atrophy (SMA) mice with commercially approved metabolism-targeting interventions leads to improved disease phenotypes,” was published in Cellular and Molecular Life Sciences.

SMA is caused in most cases by genetic mutations that reduce levels of the survival motor neuron (SMN) protein in all cells and tissues. It’s primarily characterized by progressive muscle weakness and atrophy (shrinkage).

The condition is increasingly recognized as a multi-systemic disorder that affects other organs and tissues, including the pancreas, liver, heart, and fat tissue. It can also disrupt the metabolism of blood sugar (glucose), amino acids (protein building blocks), fatty acids, and circadian rhythm (the body’s internal clock).

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While disease-modifying therapies (DMTs) have significantly extended survival and improved motor function in people with SMA, their efficacy can diminish with age, reducing quality of life. As a result, combination therapies are needed to address SMA’s multisystem nature.

Researchers in the U.K. recently reported that a nutritional intervention using an amino acid formula significantly eased persistent gastrointestinal issues in children with SMA receiving the DMT Spinraza (nusinersen).

Building on these findings, the team has now tested commercially available drugs originally designed to treat metabolic conditions. In particular, they assessed melatonin, a sleep hormone, as well as pioglitazone and insulin, both of which lower blood sugar levels.

An SMA mouse model received pioglitazone (12.5 mg/kg) and melatonin (50 mg/kg) daily by oral gavage (into the stomach) from postnatal day 5. Insulin was given subcutaneously (under the skin) every five days from postnatal day 8.

Pioglitazone and melatonin both significantly increased body weight, improved motor function, and prolonged survival in SMA mice. Insulin had a slight benefit in weight at later time points, but had no impact on motor function or survival.

“Our results demonstrate that both pioglitazone and melatonin ameliorate canonical behavioural disease phenotypes in [SMA] mice, whereas insulin treatment showed no significant improvement,” the researchers wrote.

Muscle effects differed between the drugs. Pioglitazone significantly decreased myofiber (muscle cell) size in SMA mice, while it increased myofiber area in healthy littermates. It also increased the expression (activity) of genes (Atrogin-1 or MuRF1) associated with muscle breakdown in SMA muscle.

Meanwhile, melatonin significantly increased myofiber size in SMA mice but not in healthy mice, and did not change gene expression. Insulin had no effect on myofiber size or on these genes.

“These findings suggest that melatonin prevents skeletal muscle [atrophy] without altering the gene expression,” the authors wrote.

In the spinal cord, pioglitazone and melatonin significantly decreased expression of Fas and Pmaip1, two genes linked to programmed cell death, in both SMA and healthy mice. Insulin decreased Fas expression only in healthy mice and did not affect Pmaip1. The numbers of motor neurons, the nerve cells affected in SMA, did not differ among groups.

“Our results indicate that while melatonin, pioglitazone and insulin reduce the expression of [cell death] markers in the spinal cord, this does not alter motor neuron survival in SMA mice,” the team wrote.

In the liver, fat staining showed that insulin significantly reduced lipid accumulation in SMA mice. Pioglitazone and melatonin did not significantly change it in these mice.

The researchers further examined melatonin because it had the greatest effect on survival. Melatonin treatment altered the expression of genes involved in circadian rhythm (PER1, Per2, Clock, and Bmal1), metabolism (Sirt1), cell survival (Bcl2), and glucose transport (Glut4) across several tissues. These tissues included muscle, liver, heart, spinal cord, and white and brown adipose tissue. White adipose tissue functions as the body’s primary energy storage, while brown fat is needed to maintain body temperature.

These changes depended on the tissue and on whether the mice had SMA. In SMA mice, melatonin increased UCP-1 (a marker of brown fat) and ASC-1 (a marker of white fat) only in white adipose tissue. The authors noted that the UCP-1 result suggested the browning of white fat, a shift from energy storage toward energy expenditure.

The team also tested these compounds in C. elegans, a small, transparent soil worm widely used as a genetic and developmental model organism. In SMA worms, melatonin and pioglitazone improved pharyngeal pumping (feeding) and reversals, a measure of coordination. Pioglitazone also reduced paralysis time.

“Our study provides compelling evidence supporting the therapeutic potential of metabolic-targeting interventions in mitigating the complex pathogenesis [disease processes] of SMA,” the researchers concluded. “Future studies aimed at investigating how repurposed metabolic treatments … could act synergistically together and with DMTs would be extremely valuable in light of the evolving therapeutic landscape and therapeutic needs in SMA.”