Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents

2016 ◽  
Vol 22 (8) ◽  
pp. 879-888 ◽  
Author(s):  
Dongryeol Ryu ◽  
Laurent Mouchiroud ◽  
Pénélope A Andreux ◽  
Elena Katsyuba ◽  
Norman Moullan ◽  
...  
Keyword(s):  
Muscle Function ◽  
C Elegans ◽  
Urolithin A

Urolithin A improves muscle function by inducing mitophagy in muscular dystrophy

2021 ◽  
Vol 13 (588) ◽  
pp. eabb0319
Author(s):  
Peiling Luan ◽  
Davide D’Amico ◽  
Pénélope A. Andreux ◽  
Pirkka-Pekka Laurila ◽  
Martin Wohlwend ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscular Dystrophy ◽  
Mitochondrial Dysfunction ◽  
Muscle Function ◽  
Experimental Models ◽  
Muscle Stem Cells ◽  
Expression Of Genes ◽  
Primary Myoblasts ◽  
Urolithin A ◽  
Regenerative Ability

Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy, and despite advances in genetic and pharmacological disease-modifying treatments, its management remains a major challenge. Mitochondrial dysfunction contributes to DMD, yet the mechanisms by which this occurs remain elusive. Our data in experimental models and patients with DMD show that reduced expression of genes involved in mitochondrial autophagy, or mitophagy, contributes to mitochondrial dysfunction. Mitophagy markers were reduced in skeletal muscle and in muscle stem cells (MuSCs) of a mouse model of DMD. Administration of the mitophagy activator urolithin A (UA) rescued mitophagy in DMD worms and mice and in primary myoblasts from patients with DMD, increased skeletal muscle respiratory capacity, and improved MuSCs’ regenerative ability, resulting in the recovery of muscle function and increased survival in DMD mouse models. These data indicate that restoration of mitophagy alleviates symptoms of DMD and suggest that UA may have potential therapeutic applications for muscular dystrophies.

scholarly journals Cell-autonomous and non-autonomous roles of daf-16 in muscle function and mitochondrial capacity in aging C. elegans

Aging ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 2295-2311 ◽  
Author(s):  
Hongning Wang ◽  
Phillip Webster ◽  
Lizhen Chen ◽  
Alfred L. Fisher
Keyword(s):  
Muscle Function ◽  
C Elegans ◽  
Mitochondrial Capacity

scholarly journals Axin-mediated regulation of lifespan and muscle health in C. elegans involves AMPK-FOXO signaling

2020 ◽  
Author(s):  
Avijit Mallick ◽  
Ayush Ranawade ◽  
Bhagwati P Gupta
Keyword(s):  
Muscle Function ◽  
Significant Risk ◽  
Significant Risk Factor ◽  
Mitochondrial Morphology ◽  
Dependent Manner ◽  
C Elegans ◽  
Muscle Aging ◽  
Muscle Health ◽  
Multiple Signaling

SUMMARYAging is a significant risk factor for several diseases. Studies have uncovered multiple signaling pathways that modulate the process of aging including the Insulin/IGF-1 signaling (IIS). In C. elegans the key regulator of IIS is DAF-16/FOXO whose activity is regulated by phosphorylation. A major kinase involved in DAF-16-mediated lifespan extension is the AMPK catalytic subunit homolog, AAK-2. In this study, we demonstrate a novel role of PRY-1/Axin in AAK-2 activation to regulate DAF-16 function. The pry-1 transcriptome contains many genes associated with aging and muscle function. Consistent with this, pry-1 is strongly expressed in muscles and muscle-specific overexpression of pry-1 extends the lifespan, delays muscle aging, and improves mitochondrial morphology in DAF-16-dependent manner. Furthermore, PRY-1 is necessary for AAK-2 phosphorylation. Together, our data demonstrate a crucial role of PRY-1 in maintaining the lifespan and muscle health. Since muscle health declines with age, our study offers new possibilities to manipulate Axin function to delay muscle aging and improve lifespan.

scholarly journals Pomegranate juice and extract extended lifespan and reduced intestinal fat deposition in Caenorhabditis elegans

2017 ◽  
Vol 87 (3-4) ◽  
pp. 149-158 ◽  
Author(s):  
Jolene Zheng ◽  
David Heber ◽  
Mingming Wang ◽  
Chenfei Gao ◽  
Steven B. Heymsfield ◽  
...  
Keyword(s):  
Caenorhabditis Elegans ◽  
Ellagic Acid ◽  
Fat Deposition ◽  
Pomegranate Juice ◽  
Control Group ◽  
Wild Type ◽  
C Elegans ◽  
Urolithin A ◽  
Extended Lifespan ◽  
Anti Oxidant

Abstract. Pomegranate juice with a high content of polyphenols, pomegranate extract, ellagic acid, and urolithin A, have anti-oxidant and anti-obesity effects in humans. Pomegranate juice extends lifespan of Drosophila melanogaster. Caenorhabditis elegans (C. elegans) (n = 6) compared to the control group in each treatment, lifespan was increased by pomegranate juice in wild type (N2, 56 %, P < 0.001) and daf-16 mutant (daf-16(mgDf50)I) (18 %, P = 0.00012), by pomegranate extract in N2 (28 %, P = 0.00004) and in daf-16(mgDf50)I (10 %, P < 0.05), or by ellagic acid (11 %, P < 0.05). Pomegranate juice reduced intestinal fat deposition (IFD) in C. elegans (n = 10) N2 (–68 %, P = 0.0003) or in the daf-16(mgDf50)I (–33 %, P = 0.0034). The intestinal fat deposition was increased by pomegranate extract in N2 (137 %, P < 0.0138) and in daf-16(mgDf50)I (26 %, P = 0.0225), by ellagic acid in N2 (66 %, P < 0.0001) and in daf-16(mgDf50)I (74 %, P < 0.0001), or by urolithin A in N2 (57 %, P = 0.0039) and in daf-16(mgDf50)I (43 %, P = 0.0001). These effects were partially mediated by the daf-16 pathway. The data may offer insights to human aging and obesity due to homology with C. elegans.

scholarly journals The Role of Calcium Leak in Age-Dependent Loss of C. Elegans Muscle Function

2017 ◽  
Vol 112 (3) ◽  
pp. 232a
Author(s):  
Frances M. Forrester ◽  
Alisa Umanskaya ◽  
Wenjun Xie ◽  
Steven Reiken ◽  
Qi Yuan ◽  
...  
Keyword(s):  
Muscle Function ◽  
C Elegans ◽  
Age Dependent

scholarly journals Role of oxidation of excitation-contraction coupling machinery in age-dependent loss of muscle function in C. elegans

2021 ◽  
Author(s):  
Haikel Dridi ◽  
Frances Forrester ◽  
Alisa Umanskaya ◽  
Wenjun Xie ◽  
Steven Reiken ◽  
...  
Keyword(s):  
Exercise Capacity ◽  
Muscle Function ◽  
Body Wall ◽  
Body Wall Muscle ◽  
Macromolecular Complex ◽  
Mammalian Skeletal Muscle ◽  
Dependent Manner ◽  
C Elegans ◽  
Reduced Body ◽  
Age Dependent

ABSTRACTAge-dependent loss of body wall muscle function and impaired locomotion occur within 2 weeks in C. elegans; however, the underlying mechanism has not been fully elucidated. In humans, age-dependent loss of muscle function occurs at about 80 years of age and has been linked to dysfunction of ryanodine receptor (RyR)/intracellular calcium (Ca2+) release channels on the sarcoplasmic reticulum (SR). Mammalian skeletal muscle RyR1 channels undergo age-related remodeling due to oxidative overload, leading to loss of the stabilizing subunit calstabin1 (FKBP12) from the channel macromolecular complex. This destabilizes the closed state of the channel resulting in intracellular Ca2+ leak, reduced muscle function, and impaired exercise capacity. We now show that the C. elegans RyR homolog, UNC-68, exhibits a remarkable degree of evolutionary conservation with mammalian RyR channels and similar age-dependent dysfunction. Like RyR1 in mammals UNC-68 encodes a protein that comprises a macromolecular complex which includes the calstabin1 homolog FKB-2 and is immunoreactive with antibodies raised against the RyR1 complex. Further, as in aged mammals, UNC-68 is oxidized and depleted of FKB-2 in an age-dependent manner, resulting in “leaky” channels, depleted SR Ca2+ stores, reduced body wall muscle Ca2+ transients, and age-dependent muscle weakness. FKB-2 (ok3007)-deficient worms exhibit reduced exercise capacity. Pharmacologically induced oxidization of UNC-68 and depletion of FKB-2 from the channel independently caused reduced body wall muscle Ca2+ transients. Preventing FKB-2 depletion from the UNC-68 macromolecular complex using the Rycal drug S107 improved muscle Ca2+ transients and function. Taken together, these data suggest that UNC-68 oxidation plays a role in age-dependent loss of muscle function. Remarkably, this age-dependent loss of muscle function induced by oxidative overload, which takes ~2 years in mice and ~80 years in humans, occurs in less than 2-3 weeks in C. elegans, suggesting that reduced anti-oxidant capacity may contribute to the differences in life span amongst species.

scholarly journals C. elegans Agrin Is Expressed in Pharynx, IL1 Neurons and Distal Tip Cells and Does Not Genetically Interact with Genes Involved in Synaptogenesis or Muscle Function

PLoS ONE ◽  
2007 ◽  
Vol 2 (8) ◽  
pp. e731 ◽  
Author(s):  
Ana Hrus ◽  
Gordon Lau ◽  
Harald Hutter ◽  
Susanne Schenk ◽  
Jacqueline Ferralli ◽  
...  
Keyword(s):  
Muscle Function ◽  
C Elegans ◽  
Distal Tip Cells ◽  
Tip Cells
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