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 -
TY - JOUR
A1 - Nowotny, Kerstin
A1 - Castro, Jose Pedro
A1 - Hugo, Martin
A1 - Braune, Sabine
A1 - Weber, Daniela
A1 - Pignitter, Marc
A1 - Somoza, Veronika
A1 - Bornhorst, Julia
A1 - Schwerdtle, Tanja
A1 - Grune, Tilman
T1 - Oxidants produced by methylglyoxal-modified collagen trigger ER stress and apoptosis in skin fibroblasts
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 - Methylglyoxal (MG), a highly reactive dicarbonyl, interacts with proteins to form advanced glycation end products (AGEs). AGEs include a variety of compounds which were shown to have damaging potential and to accumulate in the course of different conditions such as diabetes mellitus and aging. After confirming collagen as a main target for MG modifications in vivo within the extracellular matrix, we show here that MG-collagen disrupts fibroblast redox homeostasis and induces endoplasmic reticulum (ER) stress and apoptosis. In particular, MG-collagen-induced apoptosis is associated with the activation of the PERK-eIF2 alpha pathway and caspase-12. MG-collagen contributes to altered redox homeostasis by directly generating hydrogen peroxide and oxygen-derived free radicals. The induction of ER stress in human fibroblasts was confirmed using collagen extracts isolated from old mice in which MG-derived AGEs were enriched. In conclusion, MG-derived AGEs represent one factor contributing to diminished fibroblast function during aging.
KW - Advanced glycation end products
KW - Aging
KW - Apoptosis
KW - Collagen
KW - ER stress
KW - Methylglyoxal
KW - Redox homeostasis
Y1 - 2018
U6 - https://doi.org/10.1016/j.freeradbiomed.2018.03.022
SN - 0891-5849
SN - 1873-4596
VL - 120
SP - 102
EP - 113
PB - Elsevier
CY - New York
ER -
TY - JOUR
A1 - Henkel, Janin
A1 - Coleman, Charles Dominic
A1 - Schraplau, Anne
A1 - Jöhrens, Korinna
A1 - Weber, Daniela
A1 - Castro, Jose Pedro
A1 - Hugo, Martin
A1 - Schulz, Tim Julius
A1 - Krämer, Stephanie
A1 - Schürmann, Annette
A1 - Püschel, Gerhard Paul
T1 - Induction of Steatohepatitis (NASH) with Insulin Resistance in Wild-type B6 Mice by a Western-type Diet Containing Soybean Oil and Cholesterol
JF - Molecular medicine
N2 - Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are hepatic manifestations of the metabolic syndrome. Many currently used animal models of NAFLD/NASH lack clinical features of either NASH or metabolic syndrome such as hepatic inflammation and fibrosis (e.g., high-fat diets) or overweight and insulin resistance (e.g., methionine-choline-deficient diets), or they are based on monogenetic defects (e.g., ob/ob mice). In the current study, a Western-type diet containing soybean oil with high n-6-PUFA and 0.75% cholesterol (SOD + Cho) induced steatosis, inflammation and fibrosis accompanied by hepatic lipid peroxidation and oxidative stress in livers of C57BL/6-mice, which in addition showed increased weight gain and insulin resistance, thus displaying a phenotype closely resembling all clinical features of NASH in patients with metabolic syndrome. In striking contrast, a soybean oil-containing Western-type diet without cholesterol (SOD) induced only mild steatosis but not hepatic inflammation, fibrosis, weight gain or insulin resistance. Another high-fat diet, mainly consisting of lard and supplemented with fructose in drinking water (LAD + Fru), resulted in more prominent weight gain, insulin resistance and hepatic steatosis than SOD + Cho, but livers were devoid of inflammation and fibrosis. Although both LAD + Fru-and SOD + Cho-fed animals had high plasma cholesterol, liver cholesterol was elevated only in SOD + Cho animals. Cholesterol induced expression of chemotactic and inflammatory cytokines in cultured Kupffer cells and rendered hepatocytes more susceptible to apoptosis. In summary, dietary cholesterol in the SOD + Cho diet may trigger hepatic inflammation and fibrosis. SOD + Cho-fed animals may be a useful disease model displaying many clinical features of patients with the metabolic syndrome and NASH.
KW - Nonalcoholic Steatohepatitis (NASH)
KW - Typical Western Diet
KW - Nonalcoholic Fatty Liver Disease (NAFLD)
KW - Dietary Cholesterol
KW - Kupffer Cells
Y1 - 2017
U6 - https://doi.org/10.2119/molmed.2016.00203
SN - 1076-1551
SN - 1528-3658
VL - 23
SP - 70
EP - 82
PB - Feinstein Inst. for Medical Research
CY - Manhasset
ER -
TY - JOUR
A1 - Fernando, Raquel
A1 - Drescher, Cathleen
A1 - Nowotny, Kerstin
A1 - Grune, Tilman
A1 - Castro, Jose Pedro
T1 - Impaired proteostasis during skeletal muscle aging
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 - Aging is a complex phenomenon that has detrimental effects on tissue homeostasis. The skeletal muscle is one of the earliest tissues to be affected and to manifest age-related changes such as functional impairment and the loss of mass. Common to these alterations and to most of tissues during aging is the disruption of the proteostasis network by detrimental changes in the ubiquitin-proteasomal system (UPS) and the autophagy-lysosomal system (ALS). In fact, during aging the accumulation of protein aggregates, a process mainly driven by increased levels of oxidative stress, has been observed, clearly demonstrating UPS and ALS dysregulation. Since the UPS and ALS are the two most important pathways for the removal of misfolded and aggregated proteins and also of damaged organelles, we provide here an overview on the current knowledge regarding the connection between the loss of proteostasis and skeletal muscle functional impairment and also how redox regulation can play a role during aging. Therefore, this review serves for a better understanding of skeletal muscle aging in regard to the loss of proteostasis and how redox regulation can impact its function and maintenance.
KW - Skeletal muscle
KW - Proteostasis
KW - Proteasome and lysosome
KW - Oxidative stress
KW - Redox regulation
KW - Aging
Y1 - 2018
U6 - https://doi.org/10.1016/j.freeradbiomed.2018.08.037
SN - 0891-5849
SN - 1873-4596
VL - 132
SP - 58
EP - 66
PB - Elsevier
CY - New York
ER -
TY - JOUR
A1 - Fernando, Raquel
A1 - Drescher, Cathleen
A1 - Deubel, Stefanie
A1 - Jung, Tobias
A1 - Ost, Mario
A1 - Klaus, Susanne
A1 - Grune, Tilman
A1 - Castro, Jose Pedro
T1 - Low proteasomal activity in fast skeletal muscle fibers is not associated with increased age-related oxidative damage
JF - Experimental gerontology
N2 - The skeletal muscle is a crucial tissue for maintaining whole body homeostasis. Aging seems to have a disruptive effect on skeletal muscle homeostasis including proteostasis. However, how aging specifically impacts slow and fast twitch fiber types remains elusive. Muscle proteostasis is largely maintained by the proteasomal system. Here we characterized the proteasomal system in two different fiber types, using a non-sarcopenic aging model. By analyzing the proteasomal activity and amount, as well as the polyubiquitinated proteins and the level of protein oxidation in Musculus soleus (Sol) and Musculus extensor digitorum longus (EDL), we found that the slow twitch Sol muscle shows an overall higher respiratory and proteasomal activity in young and old animals. However, especially during aging the fast twitch EDL muscle reduces protein oxidation by an increase of antioxidant capacity. Thus, under adaptive non-sarcopenic conditions, the two fibers types seem to have different strategies to avoid age-related changes.
KW - Proteasomal system
KW - Skeletal muscle
KW - Fast and slow fibers
KW - Polyubiquitination
KW - Oxidized proteins
KW - Antioxidants
KW - Aging
KW - Mitochondrial respiration
Y1 - 2018
U6 - https://doi.org/10.1016/j.exger.2018.10.018
SN - 0531-5565
SN - 1873-6815
VL - 117
SP - 45
EP - 52
PB - Elsevier
CY - Oxford
ER -
TY - JOUR
A1 - Castro, Jose Pedro
A1 - Wardelmann, Kristina
A1 - Grune, Tilman
A1 - Kleinridders, Andre
T1 - Mitochondrial Chaperones in the Brain
BT - safeguarding Brain Health and Metabolism?
JF - Frontiers in Endocrinology
N2 - The brain orchestrates organ function and regulates whole body metabolism by the concerted action of neurons and glia cells in the central nervous system. To do so, the brain has tremendously high energy consumption and relies mainly on glucose utilization and mitochondrial function in order to exert its function. As a consequence of high rate metabolism, mitochondria in the brain accumulate errors over time, such as mitochondrial DNA (mtDNA) mutations, reactive oxygen species, and misfolded and aggregated proteins. Thus, mitochondria need to employ specific mechanisms to avoid or ameliorate the rise of damaged proteins that contribute to aberrant mitochondrial function and oxidative stress. To maintain mitochondria homeostasis (mitostasis), cells evolved molecular chaperones that shuttle, refold, or in coordination with proteolytic systems, help to maintain a low steady-state level of misfolded/aggregated proteins. Their importance is exemplified by the occurrence of various brain diseases which exhibit reduced action of chaperones. Chaperone loss (expression and/or function) has been observed during aging, metabolic diseases such as type 2 diabetes and in neurode-generative diseases such as Alzheimer's (AD), Parkinson's (PD) or even Huntington's (HD) diseases, where the accumulation of damage proteins is evidenced. Within this perspective, we propose that proper brain function is maintained by the joint action of mitochondrial chaperones to ensure and maintain mitostasis contributing to brain health, and that upon failure, alter brain function which can cause metabolic diseases.
KW - insulin signaling
KW - brain
KW - chaperones
KW - mitochondria homeostasis
KW - mitochondrial dysfunction
KW - neurodegeneration
Y1 - 2018
U6 - https://doi.org/10.3389/fendo.2018.00196
SN - 1664-2392
VL - 9
PB - Frontiers Research Foundation
CY - Lausanne
ER -
TY - JOUR
A1 - Castro, Jose Pedro
A1 - Fernando, Raquel
A1 - Reeg, Sandra
A1 - Meinl, Walter
A1 - Almeida, Henrique
A1 - Grune, Tilman
T1 - Non-enzymatic cleavage of Hsp90 by oxidative stress leads to actin aggregate formation
BT - A novel gain-of-function mechanism
JF - Redox Biology
N2 - Aging is accompanied by the accumulation of oxidized proteins. To remove them, cells employ the proteasomal and autophagy-lysosomal systems; however, if the clearance rate is inferior to its formation, protein aggregates form as a hallmark of proteostasis loss. In cells, during stress conditions, actin aggregates accumulate leading to impaired proliferation and reduced proteasomal activity, as observed in cellular senescence. The heat shock protein 90 (Hsp90) is a molecular chaperone that binds and protects the proteasome from oxidative inactivation. We hypothesized that in oxidative stress conditions a malfunction of Hsp90 occurs resulting in the aforementioned protein aggregates. Here, we demonstrate that upon oxidative stress Hsp90 loses its function in a highly specific non-enzymatic iron-catalyzed oxidation event and its breakdown product, a cleaved form of Hsp90 (Hsp90cl), acquires a new function in mediating the accumulation of actin aggregates. Moreover, the prevention of Hsp90 cleavage reduces oxidized actin accumulation, whereas transfection of the cleaved form of Hsp90 leads to an enhanced accumulation of oxidized actin. This indicates a clear role of the Hsp90cl in the aggregation of oxidized proteins.
KW - Oxidative stress
KW - Protein oxidation
KW - Heat shock protein 90
KW - Proteasome
KW - Protein aggregates
Y1 - 2019
U6 - https://doi.org/10.1016/j.redox.2019.101108
SN - 2213-2317
VL - 21
PB - Elsevier
CY - Amsterdam
ER -