Abstract
Sarcopenia is linked with impaired adaptive responses to exercise in aging skeletal muscle. The unfolded protein response (UPR) is an important intramyocellular molecular response pathway that is activated by exercise. The influence of age on skeletal muscle adaptive UPR in response to exercise, and the relationship to other key exercise-responsive regulatory pathways is not well-understood. We evaluated age-related changes in transcriptional markers of UPR activation following a single bout of resistance exercise in 12 young (27 ± 5yrs) and 12 older (75 ± 5yrs) healthy men and women. At baseline, there were modest differences in expression of UPR-related genes in young and older adults. Following exercise, transcriptional markers of UPR pathway activation were attenuated in older adults compared to young based on specific salient UPR-related genes and gene set enrichment analysis. The coordination of post-exercise transcriptional patterns between the UPR pathway, p53/p21 axis of autophagy, and satellite cell differentiation were less evident in older compared to young adults. In conclusion, transcriptomic analysis revealed an age-related decline in the adaptive UPR transcriptional response following a single bout of exercise that could contribute to impaired exercise responsiveness with age.
Highlights
Aging is associated with the loss of skeletal muscle mass, quality, and function; decrements that have a negative influence on health span [1]
Expression of phosphorylating proteins that are indicative of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) pathway activation typically peak at 48 hours post-exercise [4, 5], which could explain why no differences were detected in the present study
Stress response pathways are critical to maintaining healthspan, yet many of these pathways are impaired with aging [31] in conjunction with skeletal muscle impairments commonly observed after the seventh decade of life [32]
Summary
Aging is associated with the loss of skeletal muscle mass, quality, and function; decrements that have a negative influence on health span [1]. Resistance exercise improves muscle mass and function, but there is emerging evidence that the molecular and cellular responses to anabolic stimuli (e.g., exercise and nutrition) are attenuated in older adults; a phenomenon termed anabolic resistance [2]. In the quest to understand the molecular drivers of agerelated anabolic resistance, the physiological unfolded protein response (UPR) has emerged as a key regulatory pathway in skeletal muscle protein quality control and adaptations to exercise [3,4,5,6]. Evidence points to altered UPR as an explanation for age and disease related changes in protein folding and accumulation and aggregation of proteins within the endoplasmic reticulum (ER) [7,8,9,10]. Accumulation of misfolded proteins in the ER lumen trigger ER stress and subsequent initiation of the UPR, which is mediated by three ER transmembrane sensors: RNA-dependent protein kinase-like ER eukaryotic translation initiation factor 2 alpha kinase (PERK), inositol-requiring protein 1 (IRE1), and activating transcription factor-6 (ATF6)
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