P.275Determination of protein markers in skeletal muscle of SMA type 3 patients

Abstract

Spinal muscular atrophy (SMA) is a progressive, recessively inherited neuromuscular disease characterized by the degeneration of lower motor neurons in the spinal cord and brainstem. The reduction of the ubiquitously-expressed survival motor neuron (SMN) protein leads to weakness and muscle atrophy. While the genetic basis of SMA is well described, the tissue specific molecular pathways underlying SMA are still not fully understood and identification of marker proteins in human vulnerable tissue such as skeletal muscle is still lacking. Motor function in SMA patients may be additionally improved by targeting skeletal muscle to reduce atrophy and improve muscle strength. Development of therapeutic approaches targeting the muscle tissue has been hindered by lack of understanding of the mechanisms involved in muscular disease pathogenesis and progression. Aiming to overcome this lack of knowledge, we utilized label-free proteomics to identify the proteomic signature in neurologically-affected vastus muscle obtained from three patients with genetically proven SMA type 3. We identified 50 proteins of altered abundance (45 were increased and 5 decreased) representing potential skeletal muscle markers of SMA type 3. Functions of vulnerable proteins suggest a profound mitochondrial vulnerability and thus support the concept that metabolic alterations could be novel mechanisms in muscular involvement in SMA type 3 patients. A greater knowledge of the molecular basis of SMA pathogenesis in muscle tissue, here investigated in SMA type 3 muscle, is important for the development of potential therapeutic approaches.