Alpha B-Crystallin in Muscle Disease Prevention: The Role of Physical Activity

Abstract

HSPB5 or alpha B-crystallin (CRYAB), originally identified as lens protein, is one of the most widespread and represented of the human small heat shock proteins (sHSPs). It is greatly expressed in tissue with high rates of oxidative metabolism, such as skeletal and cardiac muscles, where HSPB5 dysfunction is associated with a plethora of human diseases. Since HSPB5 has a major role in protecting muscle tissues from the alterations of protein stability (i.e., microfilaments, microtubules, and intermediate filament components), it is not surprising that this sHSP is specifically modulated by exercise. Considering the robust content and the protective function of HSPB5 in striated muscle tissues, as well as its specific response to muscle contraction, it is then realistic to predict a specific role for exercise-induced modulation of HSPB5 in the prevention of muscle diseases caused by protein misfolding. After offering an overview of the current knowledge on HSPB5 structure and function in muscle, this review aims to introduce the reader to the capacity that different exercise modalities have to induce and/or activate HSPB5 to levels sufficient to confer protection, with the potential to prevent or delay skeletal and cardiac muscle disorders.

Keywords: alpha B-crystallin; exercise; muscle diseases.

Figure 1

Schematic representation of (A) mammalian αB-crystallin protein sequence organization. Gray box: W (tryptophan), D (aspartic acid), P (proline), and F (phenylalanine) (WDPF) amino acid domain; Red bordeaux box: conserved region; orange box: alpha crystallin domain; ΛΛΛΛΛ: flexible domain; P: phosphorylated serine residues; O-GlcNA: O-linked N-acetylglucosamine site at Thr170. (B) Exemplified monomer structure (i) of full-length HSPB5. (ii) HSPB5 monomers assemble into dimers (building block) through α-crystallin domain interactions. Higher-order assemblies occur through CTR and the α-crystallin domain to form (iii) hexamers, and poorly defined NTR interactions drive the assembly of the final oligomer (iv). (C) Schematic representation of HSPB5 effects/localization within skeletal muscle tissue. HSPB5 is proposed to function at different levels of interrelated cellular pathways, avoiding cytotoxic effects of protein aggregates and apoptosis, as well as preserving sarcomere microstructures such as titin, desmin, actin, vimentin, and nebulette.

Figure 2

Characterization of HSPB5 upstream enhancers required for the activity of sHSPs. Exon, BE: alpha binding element, MRF: muscle regulatory factor; TATA box. These cis-elements localized in the intergenic region of HSPB5 contain the DNA-binding sites or protein binding complexes by which known transcription factors (e.g., AP1, CREB, RORA, AP2F, PAX3) regulate sHSP expression.

Figure 3

Schematic representation of (A) HSPB5 physical association/direct interaction with numerous targets and (B) the predominant biological functions resulting from the gene set network. Details are given in Table 2. Biological databases of protein–protein interactions (IntAct), followed by BiNGO, a plug-in of Cytoscape 3.8.2 software are used for the Gene Ontology analysis (p < 0.01, only overrepresented categories of biological processes after correction are visualized).