Alzheimer's disease (AD) is characterized by the deposition of aggregated amyloid-beta (Aβ), which triggers a cellular stress response called the unfolded protein response (UPR). The UPR signaling pathway is a cellular defense system for dealing with the accumulation of misfolded proteins but switches to apoptosis when endoplasmic reticulum (ER) stress is prolonged. ER stress is involved in neurodegenerative diseases including AD, but the molecular mechanisms of neuronal apoptosis and inflammation by Aβ-induced ER stress to exercise training are not fully understood. Here, we demonstrated that treadmill exercise (TE) prevented PS2 mutation-induced memory impairment and reduced Aβ-42 deposition through the inhibition of β-secretase (BACE-1) and its product, C-99 in cortex and/or hippocampus of aged PS2 mutant mice. We also found that TE down-regulated the expression of GRP78/Bip and PDI proteins and inhibited activation of PERK, eIF2α, ATF6α, sXBP1 and JNK-p38 MAPK as well as activation of CHOP, caspase-12 and caspase-3. Moreover, TE up-regulated the expression of Bcl-2 and down-regulated the expressions of Bax in the hippocampus of aged PS2 mutant mice. Finally, the generation of TNFα and IL-1α and the number of TUNEL-positive cells in the hippocampus of aged PS2 mutant mice was also prevented or decreased by TE. These results showed that TE suppressed the activation of UPR signaling pathways as well as inhibited the apoptotic pathways of the UPR and inflammatory response following Aβ-induced ER stress. Thus, therapeutic strategies that modulate Aβ-induced ER stress through TE could represent a promising approach for the prevention or treatment of AD.

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Cardiac myocytes are terminally differentiated cells and possess extremely limited regenerative capacity; therefore, preservation of mature cardiac myocytes throughout the individual’s entire life span contributes substantially to healthy living. Autophagy, a lysosome-dependent cellular catabolic process, is essential for normal cardiac function and mitochondria maintenance. Therefore, it may be reasonable to hypothesize that if endurance exercise promotes cardiac autophagy and mitochondrial autophagy or mitophagy, exercise-induced cardiac autophagy (EICA) or exercise-induced cardiac mitophagy (EICM) may confer propitious cellular environment and thus protect the heart against detrimental stresses, such as an ischemia–reperfusion (I/R) injury. However, although the body of evidence supporting EICA and EICM is growing, the molecular mechanisms of EICA and EICM and their possible roles in cardioprotection against an I/R injury are poorly understood. Here, we introduce the general mechanisms of autophagy in an attempt to integrate potential molecular pathways of EICA and EICM and also highlight a potential insight into EICA and EICM in cardioprotection against an I/R insult.

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Elevation of anabolism and concurrent suppression of catabolism are critical metabolic adaptations for muscular hypertrophy in response to resistance exercise (RE). Here, we investigated if RE-induced muscular hypertrophy is acquired by modulating a critical catabolic process autophagy. Male Wistar Hannover rats (14 weeks old) were randomly assigned to either sedentary control (SC, n = 10) or resistance exercise (RE, n = 10). RE elicited significant hypertrophy of flexor digitorum profundus (FDP) muscles in parallel with enhancement in anabolic signaling pathways (phosphorylation of AKT, mTOR, and p70S6K). Importantly, RE-treated FDP muscle exhibited a significant decline in autophagy evidenced by diminished phosphorylation levels of AMPK, a decrease in LC3-II/LC3-I ratio, an increase in p62 level, and a decline in active form of lysosomal protease CATHEPSIN L in the absence of alterations of key autophagy proteins: ULK1 phosphorylation, BECLIN1, and BNIP3. Our study suggests that RE-induced hypertrophy is achieved by potentiating anabolism and restricting autophagy-induced catabolism.