Therapeutic potential of heat shock protein induction for muscular dystrophy and other muscle wasting conditions

Abstract

Duchenne muscular dystrophy is the most common and severe of the muscular dystrophies, a group of inherited myopathies caused by different genetic mutations leading to aberrant expression or complete absence of cytoskeletal proteins. Dystrophic muscles are prone to injury, and regenerate poorly after damage. Remorseless cycles of muscle fibre breakdown and incomplete repair lead to progressive and severe muscle wasting, weakness and premature death. Many other conditions are similarly characterized by muscle wasting, including sarcopenia, cancer cachexia, sepsis, denervation, burns, and chronic obstructive pulmonary disease. Muscle trauma and loss of mass and physical capacity can significantly compromise quality of life for patients. Exercise and nutritional interventions are unlikely to halt or reverse the conditions, and strategies promoting muscle anabolism have limited clinical acceptance. Heat shock proteins (HSPs) are molecular chaperones that help proteins fold back to their original conformation and restore function. Since many muscle wasting conditions have pathophysiologies where inflammation, atrophy and weakness are indicated, increasing HSP expression in skeletal muscle may have therapeutic potential. This review will provide evidence supporting HSP induction for muscular dystrophy and other muscle wasting conditions.This article is part of the theme issue 'Heat shock proteins as modulators and therapeutic targets of chronic disease: an integrated perspective'.

Keywords: heat shock proteins; muscular dystrophy; skeletal muscle wasting.

Figure 1.

Known expression levels and functions of heat shock proteins in muscular dystrophy. The absence of the dystrophin glycoprotein complex (DGC) renders dystrophic muscle fibres fragile and prone to damage, resulting in membrane tears and an influx of extracellular Ca²⁺. Compromised SERCA function contributes to an inability to buffer the increased intracellular [Ca²⁺], triggering inflammatory pathways that lead to muscle fibre degeneration. Although muscle stem cells (MuSC) can regenerate damaged fibres during the early stages of the pathology, remorseless cycles of injury/repair during the disease progression eventually overwhelm the regenerative capacity because of MuSC dysfunction, disrupted sarcomere assembly, impaired regeneration, and accumulation of connective tissue and fat. The heat shock proteins are carefully regulated both temporally and spatially during these processes. Our work and that of others suggest that modulation of HSP expression, particularly HSP72, has therapeutic potential for treating muscular dystrophy by ameliorating the dystrophic pathophysiology.