Use of an exercise challenge system to define a universal proteomic signature of muscle injury in adult individuals with diverse inherited myopathies


Translational Research

Poster Number: 155


Ben Barthel, PhD, Edgewise Therapeutics, Mads Stemmerik, PhD, University of Copenhagen, Nanna Andersen, University of Copenhagen, Sofie Skriver, University of Copenhagen, Alan Russell, PhD, Edgewise Therapeutics, John Vissing, MD, University of Copenhagen

Several inherited muscular dystrophies are defined by an enhanced injury response to exercise. However, current understanding of how muscle injury is defined depending on the underlying genetic lesion is poorly understood. We used an established exercise intervention system in a diverse set of adult individuals with myopathy to characterize proteomic signatures of injury by taking advantage of the SOMAscan 7K aptamer analysis platform. Subjects selected for the study included healthy volunteers, Becker muscular dystrophy (BMD) and Limb-girdle muscular dystrophy 2I (LGMD2I), an unrelated metabolic myopathy, McArdle disease (McA) and Limb-girdle muscular dystrophy 2L (LGMD2L). Individuals were challenged with a high intensity, bimodal exercise regimen, consisting of cycling and leg strength tests. Blood samples were collected prior to exercise and at controlled intervals up to 24 hrs post-exercise.
Using the SOMAscan analysis system, we identified novel clusters of plasma-based biomarkers that distinguished pre-exercise baseline differences from healthy controls. The exercise response of these baseline clusters was then assessed and compared across indications. We identified a significant indication-independent overlap of 26 baseline-elevated proteins that distinguished individuals with myopathy from healthy. The exercise response of this distinguishing cluster revealed two subsets of proteins, those that increased with exercise and those that were exercise-independent. Exercise-dependent biomarkers demonstrated a clear time-dependency, with >90% exhibiting maximal levels at 2-4 hrs post injury. When comparing indication-specific injury responses, BMD, LGMD2I and McA revealed a surprising degree of overlap (33 proteins), including 15 proteins that were not increased at baseline in any indication. In comparison, LGMD2L individuals demonstrated elevated baseline signature markers but no significant injury response.
These data not only provide several new biomarker candidates for distinguishing muscle injury, but highlight significant common features between indications, suggesting a common mechanism of muscle injury and breakdown, independent of underlying pathophysiology.