Disease progression reflected by blood protein signature: Study
BMD, LGMD patients' blood shows unique signature after exercise
Researchers identified a unique protein signature in the bloodstreams of adults with Becker muscular dystrophy (BMD) and limb-girdle muscular dystrophy (LGMD) that significantly differs from healthy individuals after exercise.
“We propose that a subset of circulating proteins may be more indicative of disease progression and/or therapeutic efficacy than relying solely on muscle injury biomarkers such as [creatine kinase],” the researchers wrote.
Post-exercise changes in the protein signature were predominantly related to fast-twitch muscle fibers for quick, powerful movements over slow-twitch fibers, which are better suited for endurance activities.
The study, “Universal Proteomic Signature After Exercise-Induced Muscle Injury in Muscular Dystrophies,” was published in the Annals of Clinical and Translational Neurology.
Intense physical exercise can result in muscle injury, which manifests as pain, stiffness, swelling, reduced muscle strength, and the release of muscle proteins into the bloodstream. Under normal circumstances, these symptoms and circulating muscle protein levels generally resolve within days. In MD, a group of genetic diseases marked by progressive muscle weakness and wasting, muscle damage can occur after performing normal daily activities and may be exacerbated in response to exercise.
Muscle protein and disease progression
Muscle proteins in the bloodstreams of MD patients rise more rapidly and reach higher levels than in unaffected individuals who perform the same exercise routine.
A research team led by scientists at the University of Copenhagen examined the post-exercise protein profiles in the blood of people with BMD and LGMD types R9 and R12.
The work was sponsored by Edgewise Therapeutics, which is developing sevasemten (EDG-5506), an oral therapy for people with BMD, LGMD, and Duchenne muscular dystrophy.
The study enrolled 35 adults. Nine of them had BMD, eight had LGMDR9, and nine had LGMDR12. Nine age-matched healthy individuals served as controls.
Blood samples were collected before (baseline) and after an exercise challenge that consisted of a peak cycle test, an interval training test, and a strength training test targeting the quadriceps (upper leg muscles), with a brief rest between the tests. Protein profiles were assessed using SomaScan, which measured thousands of proteins simultaneously.
In pre-exercise baseline measurements, the levels of some 60-70 proteins were higher, and about 20-30 proteins were lower, across all three MD types compared with healthy participants.
Within the proteins that distinguish MD from healthy donors, the team identified 34 that were common to all three types of MD. All elevated proteins in this baseline signature were significantly linked to muscle tissue and involved in muscle contraction and glucose metabolic pathways. Proteins at lower baseline levels were not linked to any tissue or pathway.
The results were similar and strongly correlated with the baseline (no exercise) protein signatures from blood samples of 55 BMD patients from the Newcastle Biobank in the U.K.
Following the exercise challenge, BMD and LGMDR9 patients showed a marked, time-dependent increase in the baseline signature proteins, with a peak elevation at four hours post exercise. Those with LGMDR12 had a post-exercise profile similar to that of healthy controls.
Further analysis revealed that 25 proteins showed post-exercise changes of at least 1.25 times from their pre-exercise baseline levels.
“These proteins were classified as exercise-responsive and likely represent bona fide circulating biomarkers of exercise-induced muscle injury,” the team wrote.
Before exercise, no patterns were noted regarding proteins associated with the two types of muscle fibers, fast-twitch and slow-twitch fibers. After exercise, there was an increase in fast-specific proteins in BMD and LGMDR9 patients, particularly FBP2, MyBPC2, and TNNI2. Proteins that were associated with slow-twitch fibers did not increase to the same extent, except for PGM5.
The BMD Newcastle Biobank data showed that half of the exercise-responsive proteins from the baseline signature showed a significant negative correlation with age, meaning their levels decreased with older age. These proteins were strongly associated with skeletal muscle and/or glucose metabolism. Conversely, the proteins that were not responsive to exercise did not show a correlation with age, and their distribution was significantly different from that of the muscle injury proteins.
“We have identified a small set of core proteins, which are common differentiators between [person with muscle disease] and an unaffected individual, independent of the underlying [disease processes] or the specific genetic driver,” the researchers concluded.
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