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Researchers ID Nearly Four Dozen Proteins Whose Levels Vary in Duchenne Muscular Dystrophy

NEW YORK (GenomeWeb) – A team of researchers led by SomaLogic's Larry Gold has found nearly four dozen proteins whose levels vary in the serum of patients with Duchenne muscular dystrophy as compared to people without the disorder.

As they reported in a paper to appear in the Proceedings of the National Academy of Sciences this week, the serum levels of these 44 proteins were significantly different in patients from two different independent cohorts. Some of these differences, the researchers noted, were age-dependent.

"These data suggest new protein targets and biomarkers for further DMD studies," Gold and his colleagues said in their paper. "The data also may facilitate future clinical studies designed to identify new therapeutics for DMD."

Using SomaLogic's Somascan Assay, the researchers gauged the levels of 1,125 proteins in 42 patients from the Parent Project Muscular Dystrophy-Cincinnati Children's Hospital Medical Center and 28 controls. The researchers separately examined protein levels in a cohort of 51 patients from the Cooperative International Neuromuscular Research Group-Duchenne Natural History Study and 17 matched controls.

In both cohorts, 44 biomarkers were significant associated with Duchenne muscular dystrophy, a progressive myopathy resulting from mutations in the X-lined DMD gene. Of those, 24 were significantly increased in the blood of Duchenne patients, while 20 were significantly decreased, as compared to controls, the researchers reported.

The protein biomarkers could be broadly divided into four groups based on their expression patterns and the patients' ages, which, the researchers noted, is also a proxy for disease severity.

One set of proteins was highly expressed among young Duchenne patients — between the ages of 4 and 10 — and then declined with patients' age. This group included creatine kinase-like proteins such as creatine kinase M-type, fatty acid binding protein 3, and myoglobin, among others. The researchers theorized that this early spike could be due to muscle damage, cell death, and inflammation, while the subsequent decline could correspond to the loss of muscle mass that Duchenne muscular dystrophy patients undergo with age.

Other proteins linked with Duchenne, meanwhile, were associated with inflammation and the innate immune pathway, and their expression varied with age, while others expressed at low levels were with associated with connective tissue remodeling.

In particular, the protein persephin was more highly expressed among Duchenne patients than healthy controls, the researchers reported. Persephin, they said, signals through the RET receptor tyrosine kinase-mitogen-activated protein kinase pathway and is expressed in skeletal muscle, motor neurons, and, perhaps, also in Schwann cells.

Gold and his colleagues added that persephin could be involved in the reinnervation process, and its increased expression along with decreased RET expression in Duchenne patients could be a marker for denervation/reinnervation. Further, it could be a useful clinical biomarker to gauge whether certain therapeutics stabilize muscle fibers and innervation.

"Although the significance of these particular data must first be addressed in animal models of DMD, it is exciting to think of the possibilities for these biomarkers for diseases and therapies," the researchers said.

The researchers also reported observing decreasing expression of GDF-11 in Duchenne's patients with increasing age. They added that exogenous GDF-11 has been shown to reverse age-related cardiomyopathy, and said that if GDF-11 is indeed what they've detected — rather than, for instance, its close homolog GDF-8 — it could be a candidate for mitigating the cardiomyopathy and skeletal muscle deterioration seen in Duchenne.

They cautioned again, though, that further study was needed.

Gold and his colleagues added that they plan to expand on their findings by testing additional Duchenne patients as well as Becker muscular dystrophy patients.