TY - JOUR A1 - Reeg, Sandra A1 - Jung, Tobias A1 - Castro, José Pedro A1 - Davies, Kelvin J. A. A1 - Henze, Andrea A1 - Grune, Tilman T1 - The molecular chaperone Hsp70 promotes the proteolytic removal of oxidatively damaged proteins by the proteasome JF - Free radical biology and medicine : the official journal of the Oxygen Society, a constituent member of the International Society for Free Radical Research N2 - One hallmark of aging is the accumulation of protein aggregates, promoted by the unfolding of oxidized proteins. Unraveling the mechanism by which oxidized proteins are degraded may provide a basis to delay the early onset of features, such as protein aggregate formation, that contribute to the aging phenotype. In order to prevent aggregation of oxidized proteins, cells recur to the 20S proteasome, an efficient turnover proteolysis complex. It has previously been shown that upon oxidative stress the 26S proteasome, another form, dissociates into the 20S form. A critical player implicated in its dissociation is the Heat Shock Protein 70 (Hsp70), which promotes an increase in free 20S proteasome and, therefore, an increased capability to degrade oxidized proteins. The aim of this study was to test whether or not Hsp70 is involved in cooperating with the 20S proteasome for a selective degradation of oxidatively damaged proteins. Our results demonstrate that Hsp70 expression is induced in HT22 cells as a result of mild oxidative stress conditions. Furthermore, Hsp70 prevents the accumulation of oxidized proteins and directly promotes their degradation by the 20S proteasome. In contrast the expression of the Heat shock cognate protein 70 (Hsc70) was not changed in recovery after oxidative stress and Hsc70 has no influence on the removal of oxidatively damaged proteins. We were able to demonstrate in HT22 cells, in brain homogenates from 129/SV mice and in vitro, that there is an increased interaction of Hsp70 with oxidized proteins, but also with the 20S proteasome, indicating a role of Hsp70 in mediating the interaction of oxidized proteins with the 20S proteasome. Thus, our data clearly implicate an involvement of Hsp70 oxidatively damaged protein degradation by the 20S proteasome. c) 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). KW - Protein oxidation KW - Proteasome KW - Chaperone KW - HSP70 Y1 - 2016 U6 - https://doi.org/10.1016/j.freeradbiomed.2016.08.002 SN - 0891-5849 SN - 1873-4596 VL - 99 SP - 153 EP - 166 PB - Elsevier CY - New York ER - TY - JOUR A1 - Wiedmer, Petra A1 - Jung, Tobias A1 - Castro, Jose Pedro A1 - Pomatto, Laura C. D. A1 - Sun, Patrick Y. A1 - Davies, Kelvin J. A. A1 - Grune, Tilman T1 - Sarcopenia BT - molecular mechanisms and open questions JF - Ageing research reviews : ARR N2 - Sarcopenia represents a muscle-wasting syndrome characterized by progressive and generalized degenerative loss of skeletal muscle mass, quality, and strength occurring during normal aging. Sarcopenia patients are mainly suffering from the loss in muscle strength and are faced with mobility disorders reducing their quality of life and are, therefore, at higher risk for morbidity (falls, bone fracture, metabolic diseases) and mortality.
Several molecular mechanisms have been described as causes for sarcopenia that refer to very different levels of muscle physiology. These mechanisms cover e. g. function of hormones (e. g. IGF-1 and Insulin), muscle fiber composition and neuromuscular drive, myo-satellite cell potential to differentiate and proliferate, inflammatory pathways as well as intracellular mechanisms in the processes of proteostasis and mitochondrial function.
In this review, we describe sarcopenia as a muscle-wasting syndrome distinct from other atrophic diseases and summarize the current view on molecular causes of sarcopenia development as well as open questions provoking further research efforts for establishing efficient lifestyle and therapeutic interventions. KW - molecular pathways KW - proteostasis KW - proteasome KW - autophagy KW - mitochondria, KW - muscle fibre composition Y1 - 2020 U6 - https://doi.org/10.1016/j.arr.2020.101200 SN - 1568-1637 SN - 1872-9649 VL - 65 PB - Elsevier CY - Clare ER -