Targeting Fatty Molecules Called Sphingolipids May Treat Duchenne
by |
Significantly higher levels of sphingolipids — a type of fatty molecule involved in inflammation, scarring, and cell death — are evident in the muscles of people with Duchenne muscular dystrophy and a DMD mouse model than in those of their healthy counterparts, a study shows.
Notably, suppressing sphingolipid production in these mice helped to preserve muscle function, while reducing muscle inflammation and scarring, possibly to a greater extent than standard glucocorticoid treatment.
These findings highlight sphingolipid production as a potential therapy target for DMD and suggest that combining blockers of sphingolipid production with glucocorticoids may be of more benefit than glucocorticoids alone, the researchers noted.
The study, “Inhibition of sphingolipid de novo synthesis counteracts muscular dystrophy,” was published in the journal Science Advances.
Sphingolipids, a type of bioactive fatty molecule, are involved in multiple biological processes such as cell death, cell membrane structure, inflammation, and scarring or fibrosis — all involved in DMD.
Higher-than-normal sphingolipids levels are implicated in disorders that include Alzheimer’s disease, cardiovascular disease, diabetes, and obesity, in which sphingolipids are reported to accumulate in skeletal muscle and contribute to insulin resistance.
However, little is known about the role of sphingolipids in DMD, the most common form of muscular dystrophy.
Researchers in Switzerland, along with a colleague in South Korea, provided evidence of a link between sphingolipids and muscular dystrophy, particularly DMD, reportedly for a first time.
Initially, they found the levels of enzymes involved in sphingolipid production to be significantly higher in muscle samples from people with muscular dystrophies relative to healthy individuals, with DMD associated with one of the most pronounced increases.
Analyses of muscles samples from other, independent groups of DMD patients found that higher-than-normal levels of these enzymes were present before symptom onset, becoming more pronounced after onset. This suggests that the sphingolipid production pathway is linked to DMD severity.
In addition, lab-grown myoblasts (precursor cells of skeletal muscle) from DMD patients showed significantly higher levels of sphingolipids and their metabolic intermediates than those from healthy people.
A mouse model of DMD also showed significantly increased levels of sphingolipids, metabolic intermediates, and enzymes involved in sphingolipid production in both muscle and blood, compared with healthy mice.
The researchers then assessed whether suppressing the sphingolipid production pathway could lessen DMD symptoms and restore muscle function in the mouse model.
Treating the animals for six months with myriocin — a suppressor of the first and rate-limiting enzyme of the sphingolipid production pathway — successfully lowered sphingolipid levels and partly prevented DMD-related muscle function loss relative to untreated mice, the team found.
Functional improvements were noted in the animals’ coordination, strength, and endurance, close to levels observed in healthy mice.
Reducing sphingolipid production also restored calcium balance in muscle cells — which is typically impaired in DMD — and counteracted disease-associated muscle cell membrane breakdown, muscle inflammation, and fibrosis of skeletal muscle, the heart, and the diaphragm (the dome-shaped muscle that plays a key role in breathing).
Particularly, myriocin’s effects on inflammation were found to be related to a shift toward an anti-inflammatory state in macrophages, a type of immune cell known to infiltrate the muscles of DMD patients.
The benefits of suppressing sphingolipid production in these mice were at least similar, if not superior, to those of weekly treatment with glucocorticoids, the researchers noted. Glucocorticoids, or corticosteroids, are a type of immunosuppressive treatment standard in DMD care and associated with prolonged mobility and muscle strength.
Specifically, myriocin was better than glucocorticoids at preserving muscle membrane integrity, skeletal muscle structure, and at improving functional performance.
A combination of myriocin and glucocorticoids often resulted in greater benefits than those observed with corticosteroids, the team noted.
These findings support sphingolipid production’s involvement in muscular dystrophy and that its suppression, targeting multiple disease-associated pathways simultaneously, is a potential way of treating these dystrophies.
“The multifaceted benefits achieved by correcting aberrant sphingolipid metabolism could delay the onset of symptoms, slow the progression of disease, and ultimately counteract the loss of independence associated with muscular dystrophies,” the researchers wrote.
Data support the development of new suppressors of sphingolipid production that “can be administered either alone or in combination with existing treatments,” such as glucocorticoids, they added.
Future studies are needed to better assess the potential use of sphingolipids as biomarkers of DMD and other muscular dystrophies, and to unravel the mechanisms linking sphingolipid production and these conditions.
About the Author
