Influence of heat shock proteins on skeletal muscle regeneration of old mice.

Author(s)

Tábata Leal Nascimento

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2018-06-07

Examining board members

Elen Haruka Miyabara; Alice Cristina Rodrigues; Samuel Katsuyuki Shinjo; Francemilson Goulart da Silva; Marco Carlos Uchida

• Advisor: Elen Haruka Miyabara

Abstract

Considering that the role of heat shock proteins (HSPs) on the skeletal muscle regenerative response of aged mice is still not well known, and that the treatment with O- (3-piperidino-2-hydroxy-1-propyl ) nicotinic amidoxime (BGP-15), an HSP inducer, attenuates muscle fibrosis in animals with Duchenne Muscular Dystrophy; the overexpression of HSPs in skeletal muscle induced by BGP-15 treatment and the use of inducible 70 kDa heat shock protein (HSP70) overexpressing transgenic mice could improve the muscle regenerative process through attenuation of fibrosis of regenerating muscle tissue in old mice. Therefore, the aim of this study was to investigate the influence of HSPs on muscle regenerative response in aged mice by analyzing the effects of BGP-15 treatment and HSP70 overexpression induced by transgenesis in structural, cellular, molecular and functional aspects of regenerating muscles from aged mice. At 10 days after cryolesion of the tibialis anterior (TA), BGP-15 treatment (15 mg / kg) attenuated sarcopenia, reduced the cross sectional area of regenerating myofiber from aged mice and recovered the connective tissue density and the expression of FGF in injured muscles from aged mice. Moreover, BGP-15 attenuated the force decrease in extensor digitorum longus (EDL) after injury in young mice. In addition to the beneficial effect of BGP-15 on attenuation of sarcopenia, this drug (1μM) also attenuated the loss of C2C12 myotubes exposed to the inflammatory cytokines interferon-γ and TNF-α. There was a prevention of the deficit in the initial and late differentiation of myoblasts from aged animals that overexpress HSP70. In parallel, we observed that the silencing of HSP70 in C2C12 myoblasts reduced the gene expression of MyoD and miR-326 at the beginning of the muscle differentiation process. Therefore, our results suggest that the overexpression of HSPs improves muscle regeneration in aged mice, since it accelerates the size recovery of regenerating myofibers. This effect is mediated by the attenuation of the deficit in the differentiation of myogenic precursor cells. In parallel, we demonstrated that HSP70 participates in the beginning of muscle differentiation probably through a mechanism mediated by MyoD and miR-326. In addition to the beneficial effect of the HSP inducer BGP-15 on muscle regeneration of aged animals, it attenuated sarcopenia and loss of myotubes exposed to interferon-γ and TNF-α. This latter effect is mediated by the reduction of Atrogin-1 expression. (AU)

• FAPESP's process: 13/04783-0 - The influence of heat shock proteins in the recovery of skeletal muscle of old mice
• Grantee: Tábata Leal Nascimento
• Support Opportunities: Scholarships in Brazil - Doctorate