Attenuation of p38α MAPK stress response signaling delays the in vivo aging of skeletal muscle myofibers and progenitor cells.

James Deford,Chen Z. Wang,Dmitry V. Bulavin,San Yang,Min Zhang,John Papaconstantinou,Naseem H. Ansari

doi:10.18632/aging.100802

Abstract

Functional competence and self-renewal of mammalian skeletal muscle myofibers and progenitor cells declines with age. Progression of the muscle aging phenotype involves the decline of juvenile protective factorsi.e., proteins whose beneficial functions translate directly to the quality of life, and self-renewal of progenitor cells. These characteristics occur simultaneously with the age-associated increase of p38α stress response signaling. This suggests that the maintenance of low levels of p38α activity of juvenile tissues may delay or attenuate aging. We used the dominant negative haploinsufficient p38α mouse (DN-p38α(AF/+)) to demonstrate that in vivo attenuation of p38α activity in the gastrocnemius of the aged mutant delays age-associated processes that include: a) the decline of the juvenile protective factors, BubR1, aldehyde dehydrogenase 1A (ALDH1A1), and aldehyde dehydrogenase 2 (ALDH2); b) attenuated expression of p16(Ink4a) and p19(Arf) tumor suppressor genes of the Cdkn2a locus; c) decreased levels of hydroxynonenal protein adducts, expression of COX2 and iNOS; d) decline of the senescent progenitor cell pool level and d) the loss of gastrocnemius muscle mass. We propose that elevated P-p38α activity promotes skeletal muscle aging and that the homeostasis of p38α impacts the maintenance of a beneficial healthspan.

Highlights

Progressive age-associated loss of skeletal muscle mass and function are attributed to the decline of expression of such juvenile protective factors as BubR1, a mitotic checkpoint surveillance protein [1, 2], ALDH1A1 [3,4,5,6] and ALDH2, proteins that protect against oxidative stress [7]
Low levels of P-p38α activity of juvenile tissues are associated with a physiological environment that is beneficial for efficient tissue and progenitor cell functions whereas sustained, elevated P-p38α activities promote the expression of physiological markers of the aging phenotype (AP) [14, 31]
Evidence of the physiological benefits of the attenuation of P-p38α activity is indicated by the demonstration that disruption of a single copy of the p38α gene is cardioprotective against ischemia-reperfusion [32] and that the p38α-mediated phosphorylation of HSP25 is significantly reduced in the aged (24mos) DN-p38αAF/+ mutant [24]

Summary

Introduction

Progressive age-associated loss of skeletal muscle mass and function are attributed to the decline of expression of such juvenile protective factors as BubR1, a mitotic checkpoint surveillance protein [1, 2], ALDH1A1 [3,4,5,6] and ALDH2, proteins that protect against oxidative stress [7]. The appearance of p16Ink4a and p19Arf, proteins of the Cdkn2a tumor suppressor locus, corresponds with the decline of proliferative and regenerative capacity of adult progenitor cells, i.e. the irreversible growth arrest [8,9,10,11,12,13] These age-associated changes occur simultaneously with the chronic up-regulation of p38MAPK (p38α) stress response signaling, suggesting that their state of chronic inflammation promotes the development of the aging phenotype (AP) [14,15,16,17,18,19,20].

Methods

Results

Discussion

Conclusion