DMD – BIOMARKERS & OUTCOME MEASURES: P.118 Elevation of fast, but not slow TnI in plasma from Duchenne and Becker muscular dystrophy patients suggests differential fiber response to disease

Abstract

Duchenne and Becker muscular dystrophy (DMD/BMD) are marked by an absence (DMD) or truncation (BMD) of the dystrophin protein. Dystrophin provides a structural link between the contractile elements of the sarcomere and the basement membrane of the myofiber. When absent, contraction of muscle leads to muscle stress, the opening of membrane stress channels, and myofiber degeneration. Associated with this breakdown is the leak of a number of muscle proteins into the circulation, including creatine kinase (CK), lactate dehydrogenase (LDH), myoglobin and fast skeletal troponin I. Human skeletal muscle consists of both fast (type IIa, IIx) and slow (type I) myofibers defined by their myosin isoform. Most human skeletal muscles are composed of approximately 50% slow and 50% fast fibers in a mosaic pattern. In DMD, fast fibers appear to be the first to degenerate as young patients exhibit higher levels of embryonic myosin in fast fibers (a marker of recent regeneration) and early loss of type IIx fibers. Slow fibers are commonly affected later in the disease course. Troponin I (TnI) has three different isoforms, depending on the striated muscle of origin, TNNI1 (slow skeletal), TNNI2 (fast skeletal) and TNNI3 (cardiac). We took advantage of these different isoforms to develop selective fast/slow skeletal muscle TnI ELISAs to explore the fiber-specific source of muscle proteins in circulation. Cross-sectional collections of DMD (N=132), BMD (N=52) and healthy volunteer plasma samples (N=20) were examined using these ELISAs and TnI levels compared to circulating CK. As expected, DMD patient samples exhibited the highest CK with BMD intermediate and healthy samples in the normal range. Surprisingly, only fast skeletal TNNI2 was elevated in the circulation of both BMD and DMD patients with highest levels in DMD samples and a good correlation between TNNI2 and CK. TNNI1 levels were not significantly different from healthy volunteer samples, were not different between DMD and BMD patients, and did not correlate with CK levels. This biomarker evidence suggests that different fiber types respond differently to myopathy with a marked elevation of secreted biomarker associated with fast but not slow skeletal muscle fibers. The data update our understanding of muscle biomarker levels in patients and their interpretation.