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

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.

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Faculty Opinions recommendation of Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726494017.793522514 ◽

2016 ◽

Author(s):

Dongsheng Cai

Keyword(s):

Muscle Function ◽

C Elegans ◽

Urolithin A

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

Nature Medicine ◽

10.1038/nm.4132 ◽

2016 ◽

Vol 22 (8) ◽

pp. 879-888 ◽

Cited By ~ 281

Author(s):

Dongryeol Ryu ◽

Laurent Mouchiroud ◽

Pénélope A Andreux ◽

Elena Katsyuba ◽

Norman Moullan ◽

...

Keyword(s):

Muscle Function ◽

C Elegans ◽

Urolithin A

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

Biophysical Journal ◽

10.1016/j.bpj.2016.11.1274 ◽

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

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

10.1101/2021.12.05.471286 ◽

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.

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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 ◽

10.1371/journal.pone.0000731 ◽

2007 ◽

Vol 2 (8) ◽

pp. e731 ◽

Cited By ~ 16

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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Mitochondria-Targeted Antioxidants and Skeletal Muscle Function

Antioxidants ◽

10.3390/antiox7080107 ◽

2018 ◽

Vol 7 (8) ◽

pp. 107 ◽

Cited By ~ 4

Author(s):

Sophie C. Broome ◽

Jonathan S. T. Woodhead ◽

Troy L. Merry

Keyword(s):

Skeletal Muscle ◽

Muscle Function ◽

Cell Signalling ◽

Skeletal Muscle Function ◽

Beneficial Effects ◽

Signalling Molecules ◽

Age Related ◽

And Function ◽

Very High ◽

Mitochondrial Capacity

One of the main sources of reactive oxygen species (ROS) in skeletal muscle is the mitochondria. Prolonged or very high ROS exposure causes oxidative damage, which can be deleterious to muscle function, and as such, there is growing interest in targeting antioxidants to the mitochondria in an effort to prevent or treat muscle dysfunction and damage associated with disease and injury. Paradoxically, however, ROS also act as important signalling molecules in controlling cellular homeostasis, and therefore caution must be taken when supplementing with antioxidants. It is possible that mitochondria-targeted antioxidants may limit oxidative stress without suppressing ROS from non-mitochondrial sources that might be important for cell signalling. Therefore, in this review, we summarise literature relating to the effect of mitochondria-targeted antioxidants on skeletal muscle function. Overall, mitochondria-targeted antioxidants appear to exert beneficial effects on mitochondrial capacity and function, insulin sensitivity and age-related declines in muscle function. However, it seems that this is dependent on the type of mitochondrial-trageted antioxidant employed, and its specific mechanism of action, rather than simply targeting to the mitochondria.

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Investigating the correlation of muscle function tests and sarcomere organization in C. elegans

10.1101/2021.04.13.439723 ◽

2021 ◽

Author(s):

Leila Lesanpezeshki ◽

Hiroshi Qadota ◽

Masoud Norouzi Darabad ◽

Karishma Kashyap ◽

Carla M. R. Lacerda ◽

...

Keyword(s):

Muscle Function ◽

Muscle Force ◽

Structure And Function ◽

Muscle Physiology ◽

Chemical Stimulus ◽

C Elegans ◽

Muscle Structure ◽

Membrane Attachment ◽

Sarcomere Proteins ◽

And Function

AbstractBackgroundCaenorhabditis elegans has been widely used as a model to study muscle structure and function due to many genes having human homologs. Its body wall muscle is functionally and structurally similar to vertebrate skeletal muscle with conserved molecular pathways contributing to sarcomere structure, and muscle function. However, a systematic investigation of the relationship between muscle force and sarcomere organization is lacking. Here, we investigate the contribution of various sarcomere proteins and membrane attachment components to muscle structure and function to introduce C. elegans as a model organism to study the genetic basis of muscle strength.MethodsWe employ two recently developed assays that involve exertion of muscle forces to investigate the correlation of muscle function to sarcomere organization. We utilized a microfluidic pillar-based platform called NemaFlex that quantifies the maximum exertable force and a burrowing assay that challenges the animals to move in three dimensions under a chemical stimulus. We selected 20 mutants with known defects in various substructures of sarcomeres and compared the physiological function of muscle proteins required for force generation and transmission. We also characterized the degree of sarcomere disorganization using immunostaining approaches.ResultsWe find that mutants with genetic defects in thin filaments, thick filaments and M-lines are generally weaker, and our assays are successful in detecting the functional changes in response to each sarcomere location tested. We find that the NemaFlex and burrowing assays are functionally distinct informing on different aspects of muscle physiology. Specifically, the burrowing assay has a larger bandwidth in phenotyping muscle mutants, because it could pick ten additional mutants impaired while exerting normal muscle force in NemaFlex. This enabled us to combine their readouts to develop an integrated muscle function score that was found to correlate with the score for muscle structure disorganization.ConclusionsOur results highlight the suitability of NemaFlex and burrowing assays for evaluating muscle physiology of C. elegans. Using these approaches, we discuss the importance of the studied sarcomere proteins for muscle function and structure. The scoring methodology we have developed lays the foundation for investigating the contribution of conserved sarcomere proteins and membrane attachment components to human muscle function and strength.

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