Skeletal muscle heat shock protein 70: diverse functions and therapeutic potential for wasting disorders

Sarah M Senf

doi:10.3389/fphys.2013.00330

Abstract

The stress-inducible 70-kDa heat shock protein (HSP70) is a highly conserved protein with diverse intracellular and extracellular functions. In skeletal muscle, HSP70 is rapidly induced in response to both non-damaging and damaging stress stimuli including exercise and acute muscle injuries. This upregulation of HSP70 contributes to the maintenance of muscle fiber integrity and facilitates muscle regeneration and recovery. Conversely, HSP70 expression is decreased during muscle inactivity and aging, and evidence supports the loss of HSP70 as a key mechanism which may drive muscle atrophy, contractile dysfunction and reduced regenerative capacity associated with these conditions. To date, the therapeutic benefit of HSP70 upregulation in skeletal muscle has been established in rodent models of muscle injury, muscle atrophy, modified muscle use, aging, and muscular dystrophy, which highlights HSP70 as a key therapeutic target for the treatment of various conditions which negatively affect skeletal muscle mass and function. This article will review these important findings and provide perspective on the unanswered questions related to HSP70 and skeletal muscle plasticity which require further investigation.

Highlights

The 70 kDa heat shock protein (Hsp70/HSPA) family is one of the most evolutionary conserved protein families across both prokaryotic and eukaryotic organisms (Brocchieri et al, 2008)
Among the most well studied Hsp70 family members are the constitutively expressed 70 kDa heat shock cognate protein (HSC70 or HSC73), encoded by the HSPA8 gene, and the stress-inducible Hsp70 family members, encoded for by the HSPA1A and HSPA1B genes and whose protein products differ by only two amino acids
HSP70-1/HSP72/HSPA1/HSPA1A each refers to the protein product of HSPA1A, while HSP70-2/HSPA1B both refer to the protein product of HSPA1B

Summary

INTRODUCTION

The 70 kDa heat shock protein (Hsp70/HSPA) family is one of the most evolutionary conserved protein families across both prokaryotic and eukaryotic organisms (Brocchieri et al, 2008). HSP70 could regulate later stages of the myogenic program which support differentiation and the formation of multinucleated myofibers This notion is supported by experiments from two separate studies in which introduction of an Hsp plasmid into muscles 3 or 4 days following injury enhanced the CSA and nucleation of regenerating myofibers (Moresi et al, 2009; Senf et al, 2013). As mentioned previously, additional studies detailing the effect of HSP70 overexpression and knockdown on each stage of the myogenic program are needed to better understand the role of HSP70 in these important cellular processes These experiments would be performed in both skeletal muscle cells in vitro and whole muscle, in vivo, to differentiate between the muscle cell autonomous and non-autonomous mechanisms whereby HSP70 regulates the muscle regenerative process following injury. Deficits in post-natal muscle growth in mice could play a role in this finding, since Hsp70−/− mice had www.frontiersin.org

Improved muscle morphology and function

CONCLUSION