Chaperoning heat shock proteins: proteomic analysis and relevance for normal and dystrophin-deficient muscle

Abstract

Molecular chaperones play a key role in normal muscle function and during physiological adaptations to extensive exercise and numerous forms of cellular stress. The various classes of HSPs and related chaperones are also involved in the molecular pathogenesis of a large number of neuromuscular diseases. Several MS-based proteomic studies have recently shown that the expression levels of molecular chaperones are severely altered in dystrophin-deficient muscles. Dystrophin isoform Dp427 (where Dp427 is dystrophin protein of 427 kDa) is a large membrane cytoskeletal protein and its deficiency is the primary underlying cause of Duchenne muscular dystrophy. Current efforts have focused on the establishment of a comprehensive biomarker signature of dystrophinopathy in order to improve diagnostic methods, establish reliable prognostic factors and identify novel therapeutic targets. Following an introduction into the biology of HSPs and their general role in skeletal muscle, this review outlines the proteomic profiling of molecular chaperones in dystrophinopathy. The focus is especially on the molecular fate of HSPs cardiovascular HSP (HSPB7), αBC (HSPB5), HSP70 (HSPA) and HSP90 (HSPC) in dystrophin-deficient muscles and their involvement in progressive muscular dystrophy. Furthermore, the potential usage of distinct chaperones as disease markers of secondary pathobiochemical changes for the evaluation of novel treatment options is discussed.

Keywords: Chaperone; Dystrophin; Heat shock protein; Muscular dystrophy; Stress response.