New blood biomarkers better reflect motor performance in Becker MD
2 potential biomarkers seen to outperform commonly used blood test
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In people with Becker muscular dystrophy (BMD), both an elevated creatine-to-creatinine ratio and lower myostatin muscle protein levels in the bloodstream are associated with worse motor performance, a study reported.
These two potential biomarkers predicted current functional abilities when combined with age but not disease progression over four years.
Both biomarkers also outperformed the standard creatine kinase (CK) blood test, commonly used as a diagnostic biomarker in muscular dystrophies.
“Our study demonstrates that [creatine/creatinine] and myostatin may be candidate monitoring biomarkers in BMD,” the researchers wrote.
The biomarker study, “Longitudinal Assessment of Creatine Kinase, Creatine/Creatinine ratio, and Myostatin as Monitoring Biomarkers in Becker Muscular Dystrophy,” was published in the journal Neurology.
Worse motor performance tied to higher, lower biomarker levels
Becker muscular dystrophy, known as BMD, is characterized by low levels of dystrophin, a protein that helps maintain muscle fiber strength and reduce wear and tear during muscle movements.
As a result of these low dystrophin levels, BMD patients experience progressive muscle damage and weakness — but at an older age and with milder symptoms than individuals with Duchenne muscular dystrophy (DMD), in which dystrophin is typically absent.
Because of its rarity, clinical trials have been challenging in BMD, and the wide range of functional abilities and slow disease progression among patients make capturing potential therapeutic efficacy difficult during a trial.
“Therefore, objective biomarkers are needed that could facilitate trial design and conduction,” the researchers wrote.
CK, short for creatine kinase, is a blood-based diagnostic biomarker commonly used to detect muscle damage. However, its levels in the bloodstream can vary due to muscle mass, physical activity, and seasonal changes.
Creatine is a biochemical derived from diet or produced in the liver and is constantly converted to creatinine in healthy muscle. As such, a low creatine/creatinine ratio (Cr/Crn) more closely reflects more healthy muscle tissue. Likewise, myostatin is a protein produced and released by muscle tissue, and thus related to muscle mass.
In this study, which involved 34 male BMD patients, blood samples were collected over four years. The patients had a mean age of 42.2, and 26 (about 75%) could walk without assistance. Functional tests included the North Star Ambulatory Assessment (NSAA), 10-meter run velocity (TMR), and the six-minute walking test (6MWT), which, as its name states, measures the distance an individual can walk in six minutes.
For both Cr/Crn and myostatin, the intraclass correlation coefficient was high, meaning that “the values of these 2 markers are strongly patient specific and highly heterogeneous [variable] across patients,” the team wrote. Both biomarkers were not linked with age.
CK levels were less patient-specific, and they declined with older age. Values of Cr/Crn and myostatin correlated strongly with each other but showed weak relationships with CK.
Among participants with walking abilities, high Cr/Crn, reflecting reduced creatine to creatinine conversion and less healthy muscle tissue, significantly correlated with worse functional performance across all measures — NSAA, TMR, and 6MWT.
Worse functional measures also significantly correlated with lower myostatin levels, whereas CK did not associate with any of these functional measures.
Cr/Crn and myostatin were moderately associated with the average annual change in 6MWT results. However, all other correlations between the three biomarkers, the average yearly changes, and lung function were weak. None of the biomarker values were related to dystrophin levels in muscle.
A longer follow-up, increasing the sample size and/or focusing on patients with a more similar rate of functional decline is needed to get more insight in the longitudinal relationship of Cr/Crn and myostatin with function and disease milestones in BMD.
Separately, Cr/Crn and myostatin both predicted functional abilities as assessed by the NSAA, TMR, and 6MWT. Combining these two biomarkers with age improved the predictive potential. Adding the dystrophin percentage did not improve the prediction. Lung function could be predicted by about 35% by Cr/Crn, 10% with myostatin, and 30% by both biomarkers combined with age.
“Cr/Crn and myostatin may be used as monitoring biomarkers in BMD because higher Cr/Crn and lower myostatin were associated with patients’ performance after correction for age,” the team concluded, adding, “They improved the prediction of concurrent functional performance when combined with age.”
Further study is needed, the team noted.
“A longer follow-up, increasing the sample size and/or focusing on patients with a more similar rate of functional decline is needed to get more insight in the longitudinal relationship of Cr/Crn and myostatin with function and disease milestones in BMD,” they wrote.
The study was conducted by researchers in the Netherlands and the U.K. Solid Biosciences funded the analysis of the biomarkers.
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