Targeting Essential Amino Acids Seen to Ease Muscular Symptoms of SMA in Mouse Study

Targeted therapies or dietary supplements that work to improve the metabolism of certain molecules in muscle cells may slow the progression of spinal muscular atrophy (SMA), results of an early study in mice show.

The study, “Interventions Targeting Glucocorticoid-Krüppel-like Factor 15-Branched-Chain Amino Acid Signaling Improve Disease Phenotypes in Spinal Muscular Atrophy Mice,” was published in EBioMedicine.

SMA is an inherited disease caused by genetic mutations in the SMN1 gene that lead to faulty production of the SMN protein required for nerve cells controlling motor function to work as they should.

Disease treatments have focused on overcoming its underlying genetic causes and motor nerve cell dysfunction. But changes in the behavior of other cells, such as muscle cells, and changes in overall body metabolism can also contribute to the disease’s symptoms and rate of progression.

Researchers at Keele University in the U.K. addressed the role of a specific metabolic pathway, mediated by a molecule called KLF15, in the serum and skeletal muscle of a mouse model of SMA during disease progression.

KLF15, also known as Krüppel-like factor 15, is an important regulator of genes commonly involved in the normal use of fats, sugars, and amino acids by cells. In particular, KLF15 is known to mediate the metabolism of essential amino acids — the building blocks of proteins — in muscle cells.

Researchers analyzed KLF15 levels in four samples of muscle cells collected at different disease stages — pre-symptomatic, early symptomatic, late symptomatic and end stage.

During early stages of the disease, all the samples had lower KLF15 levels compared to healthy controls. But this trend changed with disease progression: during the symptomatic phases, SMA muscle samples showed higher levels of KLF15, whereas control samples showed lower levels.

Interestingly, the changes reported in KLF15 levels in samples from healthy control mice did not correlate to SMN levels, as those remained stable throughout the study period.

Fluctuations in KLF15 levels were accompanied by changes in the levels of several genes involved in the metabolism of essential amino acids, suggesting a deregulation of this metabolic pathway in SMA. But this effect was not limited to muscle cells, as KLF15 levels increased in the liver and heart at later stages of the disease.

These findings suggest that lower activity of the KLF15-mediated essential amino acids metabolism pathway in pre-symptomatic SMA mice “is limited to skeletal muscle.” In contrast, “the increased activity in symptomatic SMA animals may be a more widespread phenomenon,” the researchers wrote.

Treating mice with prednisolone, a common glucocorticoid that is known to activate KLF15, significantly increased KLF15 levels in muscle cells during early stages of SMA. But this effect was lost during later stages — suggesting that the animals became resistant to the treatment.

Still, treated animals showed better weight gain,  a longer lifespan, and improved muscle response compared to untreated mice.

Dietary supplements with essential amino acids were also seen to be beneficial, and when used as neuromuscular decline begins led to better weight gain and survival in the SMA mice.

Additional studies are required to better understand the impact that these supplements have on whole body response.

“Future therapeutic endeavors should consider a combination of pharmacological and dietary interventions to restore GC-KLF15-BCAA-dependent muscle and metabolic homeostasis alongside SMN-specific treatment strategies,” the researchers wrote.

“The therapeutic potential of targeting metabolic perturbations by diet and commercially available drugs could have a broader implementation across other neuromuscular and metabolic disorders,” they concluded.