Approved Metabolism Drugs Rescue Disease Signs in SMA Mice

Spinal muscular atrophy has long been understood as a disease of motor neurons, a genetic condition in which the progressive loss of nerve cells that control skeletal muscles leaves infants and, in milder cases, older children and adults struggling to move, breathe and swallow. The discovery that the survival motor neuron protein, SMN, is deficient in every cell of the body was once viewed largely through a neurological lens. Over the past decade, however, researchers have assembled a compelling case that SMA is not simply a disease of the spinal cord. It is a multi-system disorder, and one of its most damaging and least well-treated dimensions is metabolic. A new study published in Cellular and Molecular Life Sciences now reports that three commercially approved, metabolism-targeting interventions—pioglitazone, melatonin and insulin—improve a range of disease phenotypes in a mouse model of SMA, offering a fresh rationale for combining metabolic therapies with the disease-modifying drugs already in clinical use.

The research, led by Melissa Bowerman of Keele University’s School of Medicine together with colleagues at the University of Hertfordshire and the Wolfson Centre for Inherited Neuromuscular Disease, builds on earlier work from the same laboratory that combined bioinformatics with drug repositioning strategies to identify compounds capable of correcting metabolic defects in SMA. Rather than starting from scratch with novel molecules, the team deliberately focused on drugs that are already approved for human use, an approach that could shorten the path from bench to bedside considerably. The three candidates that emerged—pioglitazone, a thiazolidinedione used to treat type 2 diabetes; melatonin, a hormone that regulates circadian rhythms; and insulin, the classic metabolic hormone—each target a different facet of cellular energy handling.

The experimental system at the heart of the study is the Smn2B/- mouse, a well-established model of SMA that carries a deletion of the mouse Smn gene alongside a human SMN2 transgene. This model recapitulates many features of the human disease, including motor dysfunction, muscle atrophy, shortened lifespan and systemic metabolic abnormalities. The researchers treated these mice with each of the three compounds and assessed a battery of behavioural, molecular and histological endpoints. Alongside the mouse work, they used the nematode worm Caenorhabditis elegans as a complementary in vivo platform, allowing rapid evaluation of the compounds’ effects in a second organism with conserved metabolic pathways.

The results, the team reports, were encouraging across the board, albeit to different degrees for each compound. All three drugs improved various pathological features in the SMA mice and worms, including survival, body weight, motor function, muscle size, the health of the spinal cord and the accumulation of lipids in the liver. Hepatic steatosis—the abnormal build-up of fat in liver tissue—is one of the metabolic pathologies increasingly recognised in SMA patients and models, and its improvement following treatment suggests that the compounds were acting on genuine disease-relevant biology rather than producing non-specific effects. Improvements in muscle size and spinal cord health point to benefits that extend beyond the liver into tissues central to neuromuscular function.

Of the three interventions, melatonin produced the most significant effect on survival, the endpoint that carries the greatest weight in preclinical SMA research. This finding is particularly striking because melatonin is not typically thought of as a metabolic drug; its best-known role is as a circadian signal produced by the pineal gland. Yet the study found that melatonin’s activity in SMA mice extended across several tissues, influencing molecular effectors involved in circadian rhythm regulation, glucose metabolism, mitochondrial biogenesis and the browning of white adipose tissue. Browning—the conversion of energy-storing white fat into energy-burning beige or brown fat—is a process with profound implications for systemic energy balance, and its disruption has been implicated in the metabolic dysfunction seen in SMA.

The involvement of mitochondria is another thread worth unpacking. Mitochondria are the power plants of the cell, and their biogenesis—the generation of new mitochondrial material—is governed by molecular pathways that respond to metabolic stress. In SMA, mitochondrial defects have been observed in multiple tissues, and the ability of melatonin to influence mitochondrial biogenesis suggests a mechanism by which the hormone could restore cellular energy capacity in vulnerable tissues such as muscle and liver. Similarly, its effects on glucose metabolism echo the insulin resistance and dyslipidaemia documented in SMA patients, abnormalities that current disease-modifying therapies do not adequately address.

That last point is crucial to understanding why the study matters. The last several years have seen a remarkable transformation in SMA care, with the arrival of nusinersen, an antisense oligonucleotide that modifies SMN2 splicing; onasemnogene abeparvovec, a gene therapy that delivers a functional copy of the SMN1 gene; and risdiplam, an oral SMN2 splicing modifier. These therapies have delivered dramatic gains in survival and motor function, particularly when treatment begins early. Yet they share a common limitation: they are designed to raise SMN levels, primarily benefiting the neuromuscular system, and they leave the peripheral and metabolic pathologies of the disease largely untouched. Patients treated with these drugs still exhibit metabolic abnormalities, and the peripheral tissues—skeletal muscle, liver, pancreas and adipose tissue—remain sites of ongoing dysfunction. The new study argues that this therapeutic gap is precisely where metabolism-targeted interventions could make a difference.

The concept of SMA as a metabolic disease is grounded in the biology of SMN itself. Although the protein is best known for its role in the assembly of spliceosomal ribonucleoproteins, its loss produces detectable abnormalities in tissues far removed from the motor neuron. Insulin resistance, hepatic steatosis, dyslipidaemia and circadian disruption have all been documented in SMA, and these abnormalities are not merely consequences of immobility; they appear to arise from cell-autonomous metabolic defects. Reframing SMA pathology from a neurocentric to a metabolic perspective, as the authors put it, reveals a disease landscape in which energy handling goes wrong in parallel with, and possibly contributes to, neuromuscular degeneration. On this view, correcting metabolic dysfunction is not an afterthought but a legitimate therapeutic goal in its own right.

The translational appeal of the approach lies in the fact that all three compounds are already commercially approved. Pioglitazone is prescribed worldwide for type 2 diabetes and has a well-characterised safety profile, although its use is associated with weight gain and, in some patients, concerns about fluid retention and fracture risk. Melatonin is available over the counter in many countries and is generally well tolerated. Insulin, of course, is a mainstay of diabetes management, though its use in non-diabetic patients would require careful dosing and monitoring. The authors are careful to note that the study was conducted in mouse and worm models, and that the doses, timing and combinations used in animals may not translate directly to humans. Clinical trials would be needed to establish whether these interventions, alone or in combination with existing SMN-restoring therapies, can deliver measurable benefits in patients. Nevertheless, the fact that the compounds are approved means that safety data already exist, potentially accelerating the design of early-phase studies.

The broader significance of the work may lie in the shift it represents in how the field thinks about combination therapy for SMA. Just as oncology moved from single-agent treatments to rational multi-drug regimens that attack different vulnerabilities simultaneously, neuromuscular medicine may be heading toward pairing SMN-restoring therapies with second-generation treatments aimed at specific non-neurological pathologies. The findings position metabolism, as the authors conclude, at the forefront of targets for SMA treatments and provide a strong rationale for exploring metabolism-targeted second-generation therapies to complement currently approved disease-modifying treatments. For a disease that was once considered untreatable, and which now has effective but incomplete therapies, the prospect of adding metabolic correction to the therapeutic arsenal represents a meaningful step forward—one that could matter most for the patients whose peripheral symptoms persist despite the most advanced neuromuscular interventions available today.

Subject of Research: Testing commercially approved metabolism-targeting drugs in a mouse model of spinal muscular atrophy

Article Title: Treating Smn2B/− spinal muscular atrophy (SMA) mice with commercially approved metabolism-targeting interventions leads to improved disease phenotypes

Article References: Çetin, Ö., McCallion, E., Hoolachan, J. M., Sutton, E. R., Cook, J., Al-Mozani, Y., Dhoowooah, A., Varughese, M. S., Velandia Dorta, L. F., Koomson, J., Rashid, S., Pacheco-Torres, P., Dimitriadi, M., & Bowerman, M. (2026). Treating Smn2B/− spinal muscular atrophy (SMA) mice with commercially approved metabolism-targeting interventions leads to improved disease phenotypes. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06461-1

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06461-1

Keywords: spinal muscular atrophy, metabolism, melatonin, pioglitazone, insulin, Smn2B/- mice, drug repositioning, mitochondrial biogenesis, hepatic steatosis, circadian rhythm, adipose tissue browning, combination therapy