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Cited by 81Mitochondrial Function and PathologyMuscle Physiology and DisordersAutophagy in Disease and Therapy

miR-181a regulates p62/SQSTM1, parkin, and protein DJ-1 promoting mitochondrial dynamics in skeletal muscle aging

Open access
Goljanek‐Whysall, Katarzyna, Soriano‐Arroquia, Ana, McCormick, Rachel, Chinda, Caroline, McDonagh, Brian·2020·Aging Cell
DOI 10.1111/acel.13140PMC PMC7189996

Published version of a preprint

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Abstract

One of the key mechanisms underlying skeletal muscle functional deterioration during aging is disrupted mitochondrial dynamics. Regulation of mitochondrial dynamics is essential to maintain a healthy mitochondrial population and prevent the accumulation of damaged mitochondria; however, the regulatory mechanisms are poorly understood. We demonstrated loss of mitochondrial content and disrupted mitochondrial dynamics in muscle during aging concomitant with dysregulation of miR‐181a target interactions. Using functional approaches and mito‐QC assay, we have established that miR‐181a is an endogenous regulator of mitochondrial dynamics through concerted regulation of Park2, p62/SQSTM1, and DJ‐1 in vitro. Downregulation of miR‐181a with age was associated with an accumulation of autophagy‐related proteins and abnormal mitochondria. Restoring miR‐181a levels in old mice prevented accumulation of p62, DJ‐1, and PARK2, and improved mitochondrial quality and muscle function. These results provide physiological evidence for the potential of microRNA‐based interventions for age‐related muscle atrophy and of wider significance for diseases with disrupted mitochondrial dynamics.

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Written from the paper’s full text.

TL;DR

This paper identifies miR-181a as an age-downregulated microRNA that regulates mitochondrial dynamics in skeletal muscle by targeting p62/SQSTM1 and Park2, with indirect effects on DJ-1. Restoring miR-181a in old mice reduced mitophagy-associated protein accumulation and improved mitochondrial quality, myofiber size, and muscle force.

Key findings

  • Aging muscle showed decreased mitochondrial content and abnormal mitochondria despite increased autophagy/mitophagy proteins; miR-181a was downregulated in tibialis anterior of old mice and after exercise in adult mice.
  • In C2C12 myoblasts, miR-181a overexpression increased mitophagic events and mitochondrial gene expression, while miR-181a inhibition reduced mitophagic flux and increased p62, Park2, and DJ-1 mRNAs/proteins.
  • Reporter assays confirmed p62 and Park2 as direct miR-181a targets; DJ-1 was regulated indirectly, as the GFP-DJ-1 construct did not respond to miR-181a.
  • In vivo, miR-181a treatment of old mice prevented accumulation of p62, DJ-1, and PARK2, increased mitochondrial content markers, reduced abnormal mitochondria, increased myofiber size, and restored maximum muscle force; miR-181a inhibition in adult mice decreased force and increased small fibers.

Methods

  • Label-free proteomics of tibialis anterior from adult (6 months) and old (24 months) male C57BL/6 mice, with or without 15 min isometric contractions; significant proteins were defined as fold change >2 and −10logP >20 (p < .01).
  • C2C12 myoblasts were transfected with miR-181a mimic or antagomiR-181a (100 nM, 48 hr) and treated with DMSO, 10 µM CCCP, or 100 nM bafilomycin A1; mitophagy was assessed with mito-QC and LC3/TOM20 imaging.
  • In vivo, male mice received 2 mg/kg miR-181a mimic or antagomiR three times over 4 weeks; outcomes included qPCR, Western blotting, immunostaining, SDH staining, EM, and EDL muscle force (n = 3–6, with n = 6 adult and n = 4 old for force).

Limitations

  • Stated: mitophagic flux was not directly assessed in animal models; mitochondrial biogenesis was inferred indirectly from microscopy and PGC1α, Tfam, Nd-1, and Cox-1 expression; effects in other tissues were not examined; only male mice were studied.
  • Evident: the DJ-1 reporter assay did not show direct binding, so DJ-1 regulation is inferred as indirect; sample sizes are small (n = 3–6), and no female mice were included.

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Integrity signals

Registry

Crossref · 10.1111/acel.13140

Cites

56 of 56 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 46 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    More pronounced LC3 punctae were observed in muscle from old mice.

    “Analysis of an autophagy marker LC3 revealed more pronounced LC3 punctae in muscle from old mice (Figure 2d).”
    Quote in the paperNot a substantial claim
  • Findingown data

    miR-181 family was predicted to target multiple genes associated with mitochondrial dynamics.

    “miR‐181 family was predicted to target multiple genes investigated.”
    Quote in the paperSubstantial claim
  • Findingown data

    In miR-181a-treated muscle, expression of mitochondrial biogenesis-associated genes PGC1α and Tfam was upregulated.

    “Consistently in miR‐181a‐treated muscle, the expression of these mitochondrial biogenesis‐associated genes was upregulated (Figures 5c and S5).”
    Quote in the paperSubstantial claim
  • Findingown data

    Global label-free proteomics demonstrated clear differences in proteomic content of TA muscle between quiescent or contracted muscle of adult or old mice.

    “Significantly changed proteins (fold change >2 and −10logP > 20) between quiescent or contracted muscle of adult or old mice demonstrate clear differences in the proteomic content of TA muscle (Figure 1a).”
    Quote in the paperSubstantial claim
  • Findingown data

    miR-181a treatment of old mice resulted in a nonsignificant trend for increased SDH intensity.

    “miR‐181a treatment of old mice resulted in a nonsignificant trend for increased SDH intensity (Figure 6g).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 61
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 30

  • May combine two claims.

    Findingown data

    miR-181 overexpression resulted in presence of LC3-positive punctae in DMSO-, CCCP-, and BAF-treated cells, whereas inhibition of miR-181a resulted in accumulation of LC3 and TOM20 colocalized punctae in DMSO, CCCP, and BAF-treated cells.

    “miR‐181 overexpression resulted in the presence of LC3‐positive punctae in DMSO‐, CCCP‐, and BAF‐treated cells, whereas inhibition of miR‐181a resulted in the accumulation of LC3 and TOM20 colocalized punctae in DMSO, CCCP, and BAF‐treated cells (Figure 3d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Expression of mitochondrial genes Cox I, Nd-1, and Tomm20 was increased following miR-181a overexpression and decreased in response to AM181a.

    “The expression of all the mitochondrial genes was increased following miR‐181a overexpression and decreased in response to AM181a (Figure 3g).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The major significant proteomic changes detected in TA muscle were as a result of aging, despite some changes between contracted muscle of adult and old mice.

    “Despite detected changes in the abundance of some proteins between contracted muscle of adult and old mice, the major significant proteomic changes detected were as a result of aging.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    miR-181a treatment led to significant decrease in GFP fluorescence from GFP-p62 and GFP-Park2, but not GFP-DJ-1 constructs, as compared to scrambled-treated controls.

    “miR‐181a treatment led to significant decrease in GFP fluorescence from GFP‐p62 and GFP‐Park2, but not GFP‐DJ‐1 constructs, as compared to scrambled‐treated controls (Figure 4d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    miR-181a-treated mice had a higher proportion of larger fibers, whereas AM181a treatment resulted in a higher population of smaller fibers in muscle from adult mice.

    “The relative proportion of fiber sizes within the population of fibers revealed that miR‐181a‐treated mice had a higher proportion of larger fibers, whereas AM181a treatment resulted in a higher population of smaller fibers in muscle from adult mice (Figure 6c).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Restoration of miR-181a content in muscle of old mice in vivo prevented accumulation of p62, PARK2, and DJ-1 and preserved mitochondrial content, ultimately resulting in increased myofiber size and muscle force.

    “Restoration of miR‐181a content in muscle of old mice in vivo prevented accumulation of p62, PARK2, and DJ‐1 and preserved mitochondrial content, ultimately resulting in increased myofiber size and muscle force.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    miR-181a inhibition led to a decrease, whereas miR-181a overexpression led to an increase in myofiber size from adult and old mice.

    “However, miR‐181a inhibition led to a decrease, whereas miR‐181a overexpression led to an increase in myofiber size from adult and old mice, respectively (Figure 6a,b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    miR-181a, and not miR-181b, miR-181c, or miR-181d, was downregulated in TA of mice during aging and exercise of adult mice only.

    “miR‐181a, and not miR‐181b, miR‐181c, or miR‐181d, was downregulated in TA of mice during aging and exercise of adult mice only (Figure 2g,h).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CCCP treatment decreased expression levels of miR-181a, while miR-181a mimic and antagomiR-181a increased and decreased, respectively, miR-181a levels in C2C12 cells.

    “CCCP treatment decreased expression levels of miR‐181a, while miR‐181a mimic and antagomiR‐181a (AM181a) increased and decreased, respectively, miR‐181a levels in C2C12 cells (Figure S2a).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    miR target prediction databases TargetScan, miRnet, and miRWalk identified miR-181a-5p as a putative regulator of multiple genes associated with mitochondrial dynamics: previously validated targets Park2, Sirt-1, PTEN, and Atg-5, and novel putative targets p62, DJ-1, Mfn1, Mfn2, and Tfam.

    “miR target prediction databases, TargetScan, miRnet, and miRWalk, identified miR‐181a‐5p (miR‐181a) as a putative regulator of multiple genes associated with mitochondrial dynamics: previously validated targets (highlighted in bold in Figure 3a: Park2, Sirt‐1, PTEN, and Atg‐5, and novel putative targets: p62, DJ‐1, Mfn1, Mfn2, and Tfam (Figure 3a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Inhibition of miR-181a in muscle of adult mice led to accumulation of p62 and DJ-1 mRNA, whereas overexpression of miR-181a in muscle of old mice led to reduced levels of p62, Park2, and DJ-1 mRNA as compared to control old mice to levels observed in adult mice.

    “Inhibition of miR‐181a in muscle of adult mice led to accumulation of p62 and DJ‐1 mRNA, whereas overexpression of miR‐181a in muscle of old mice led to reduced levels of p62, Park2, and DJ‐1 mRNA as compared to muscle of control old mice to levels observed in muscle of adult mice (Figure 5b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CCCP treatment increased the number of mitochondria associated with lysosomes in Scr controls, which returned to basal levels after BAF treatment.

    “CCCP treatment increased the number of mitochondria associated with lysosomes in Scr controls which returned to basal levels after BAF treatment (Figure 3e,f).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Upregulating miR-181a levels in old mice improved mitochondrial morphology, increased fiber diameter, and specific force.

    “Conversely, upregulating miR‐181a levels in old mice improved mitochondrial morphology, increased fiber diameter, and specific force.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    AM181a treatment leads to accumulation of BNIP3 or LAMP1 punctae colocalized with TOM20, demonstrating low levels of miR-181a are associated with inhibition of mitophagic flux.

    “Both experiments demonstrated that AM181a treatment leads to accumulation of BNIP3 or LAMP1 punctae colocalized with TOM20, further demonstrating that low levels of miR‐181a are associated with inhibition of mitophagic flux (Figure S3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In DMSO-treated cells, inhibition of miR-181a resulted in increased levels of p62 mRNA and accumulation of p62 protein which did not colocalize with COXIV mitochondrial marker.

    “However, in DMSO‐treated cells, inhibition of miR‐181a resulted in increased levels of p62 mRNA and accumulation of p62 protein which did not colocalize with COXIV mitochondrial marker (Figure 4a,b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CCCP treatment resulted in formation of LC3 punctae, while BAF treatment resulted in accumulation of LC3 punctae colocalized with TOM20.

    “CCCP treatment resulted in formation of LC3 punctae, while BAF treatment resulted in the accumulation of LC3 punctae colocalized with TOM20 (Figure 3d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In vitro experiments confirmed miR-181a targets p62 and Park2, and demonstrated that miR-181a regulates mitophagic flux.

    “In vitro experiments confirmed miR‐181a targets p62 and Park2, and demonstrated that miR‐181a regulates mitophagic flux.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    In muscle of old mice, miR-181a treatment led to increased expression of mitochondrial genes CoxI and Nd-1 as a marker of mitochondrial content.

    “Consistently, in muscle of old mice, miR‐181a treatment led to increased expression of mitochondrial genes as a marker of mitochondrial content (Figure 5c).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The most significantly changed pathways in muscle during aging were downregulation of mitochondrial proteins and upregulation of contractile apparatus proteins.

    “The most significantly changed pathways in muscle during aging were downregulation of mitochondrial proteins and upregulation of contractile apparatus proteins with age (Figure 1b,c).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Maximum and specific force was decreased in muscle of adult mice treated with AM181a, whereas miR-181a overexpression in muscle of old mice restored maximum muscle force.

    “Maximum and specific force was decreased in muscle of adult mice treated with AM181a, whereas miR‐181a overexpression in muscle of old mice restored maximum muscle force (Figure 6h).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Muscle of control old mice was characterized by increased p62, DJ-1, and PARK2-positive myofibers compared to control adult mice, confirming disrupted or inhibited autophagy during aging.

    “The muscle of control old mice was characterized by the presence of increased p62, DJ‐1, and PARK2‐positive myofibers as compared to the muscle of control adult mice, confirming disrupted or inhibited autophagy during aging (Figure 5a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In CCCP-treated cells, inhibition of miR-181a resulted in accumulation of p62, DJ-1, and Park-2 mRNAs and protein with reduced colocalization with COXIV.

    “In CCCP‐treated cells, inhibition of miR‐181a resulted in accumulation of p62, DJ‐1, and Park‐2 mRNAs and protein with reduced colocalization with COXIV.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    miR-181a treatment of old mice led to a lower proportion of structurally abnormal mitochondria and decreased abundance of abnormally large mitochondria.

    “miR‐181a treatment of old mice led to a lower proportion of structurally abnormal mitochondria and decreased the abundance of abnormally large mitochondria (Figure 6d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Quantitative proteomic data revealed reduced mitochondrial protein content with age, concomitant with upregulation of mitophagy-associated proteins.

    “Quantitative proteomic data revealed a reduced mitochondrial protein content with age, concomitant with the upregulation of mitophagy‐associated proteins.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A decrease in miR-181a expression resulted in increased expression of autophagy-associated genes, a decrease in fiber diameter, and specific muscle force in adult mice mimicking aging.

    “In summary, a decrease in miR‐181a expression resulted in increased expression of autophagy‐associated genes, a decrease in fiber diameter, and specific muscle force in adult mice mimicking aging.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    AM181a treatment of adult mice led to increased number of p62-, DJ-1-, and PARK2-positive myofibers, whereas fewer p62-, DJ-1-, and PARK2-positive myofibers were detected in miR-181a-treated old mice compared to their respective controls.

    “AM181a treatment of adult mice led to increased number of p62‐, DJ‐1‐, and PARK2‐positive myofibers, whereas fewer p62‐, DJ‐1‐, and PARK2‐positive myofibers were detected in miR‐181a‐treated old mice compared to their respective controls (Figure 5a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    A higher proportion of LC3-positive myofibers was detected in muscle of control old mice and AM181a-treated adult and old mice, with almost no LC3-positive fibers detected in adult saline and miR-181a-treated mice.

    “Moreover, a higher proportion of LC3‐positive myofibers was detected in muscle of control old mice and AM181a‐treated adult and old mice, with almost no LC3‐positive fibers detected in adult saline and miR‐181a‐treated mice (Figure 6e).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Muscle during aging accumulates key regulators of the mitophagic machinery and has defective mitochondrial dynamics resulting in accumulation of abnormal mitochondria and loss of mitochondrial content.

    “Together, our data demonstrate an accumulation of key regulators of the mitophagic machinery in muscle during aging and defective mitochondrial dynamics resulting in accumulation of abnormal mitochondria and loss of mitochondrial content.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    miR-181a regulates myofiber size and muscle force.

    “Finally, we have shown that miR‐181a regulates myofiber size and muscle force: Adult and old mice treated with AM181a or miR‐181a had significant changes in the expression of genes linked with mitochondrial dynamics, mitochondrial quality, and muscle fiber diameter and specific force of muscle (Figure 6).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Restored expression of miR-181a in the muscle of old mice was related with increased mitochondrial content and improved mitochondrial quality.

    “was related with increased mitochondrial content and improved mitochondrial quality”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Low levels of miR-181a in aging muscle were associated with accumulation of its target proteins and stalled autophagy.

    “Low levels of miR‐181a in aging muscle were associated with accumulation of its target proteins and stalled autophagy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Adult and old mice treated with AM181a or miR-181a had significant changes in the expression of genes linked with mitochondrial dynamics, mitochondrial quality, and muscle fiber diameter and specific force of muscle.

    “Adult and old mice treated with AM181a or miR‐181a had significant changes in the expression of genes linked with mitochondrial dynamics, mitochondrial quality, and muscle fiber diameter and specific force of muscle (Figure 6).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    microRNAs are small 19-25 nt long noncoding RNAs that regulate gene expression post-transcriptionally through binding to complementary target sites within mRNAs, usually 3′UTRs, leading to mRNA degradation and/or inhibition of mRNA translation.

    “microRNAs (miRs) are small 19–25 nt long noncoding RNAs that regulate gene expression post‐transcriptionally through binding to complementary target sites within mRNAs, usually 3′UTRs, leading to mRNA degradation and/or inhibition of mRNA translation (Bethune, Artus‐Revel, & Filipowicz, 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bethune, Artus‐Revel, & Filipowicz, 2012

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Accumulation of damaged or dysfunctional mitochondria increases oxidation of contractile proteins in muscle, associated with disrupted balance between anabolic and catabolic processes and ultimately sarcopenia.

    “Moreover, accumulation of damaged or dysfunctional mitochondria increases the oxidation of contractile proteins in muscle, associated with disrupted balance between anabolic and catabolic processes and ultimately sarcopenia (Carnio et al., 2014; O'Leary, Vainshtein, Iqbal, Ostojic, & Hood, 2013).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Carnio et al., 2014

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    • cites O'Leary, Vainshtein, Iqbal, Ostojic, & Hood, 2013

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Integration of mitochondrial biogenesis and selective degradation via mitophagy is essential for preservation of healthy muscle, and disruption of this balance can result in alterations in muscle bioenergetics and loss of muscle mass and function.

    “The integration of mitochondrial biogenesis and selective degradation via mitophagy is essential for the preservation of healthy muscle, and disruption of this balance can result in alterations in muscle bioenergetics and loss of muscle mass and function (Hood, Memme, Oliveira, & Triolo, 2019).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hood, Memme, Oliveira, & Triolo, 2019

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Expression of a number of specific miRs changes in skeletal muscle during exercise and aging.

    “The expression of a number of specific miRs changes in skeletal muscle during exercise and aging (Kim et al., 2014; Nielsen et al., 2010).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Kim et al., 2014

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    • cites Nielsen et al., 2010

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A decrease in expression of regulators of mitochondrial fusion (Mfn1, Mfn2, Opa1) and fission (Drp1) has been reported in sedentary old individuals, but in senior sportsmen with an active lifestyle their expression levels are comparable to younger individuals.

    “A decrease in the expression of regulators of mitochondrial fusion (Mfn1, Mfn2, and Opa1) and fission (Drp1) has been reported in sedentary old individuals, but in senior sportsmen that have maintained an active lifestyle their expression levels are comparable to younger individuals (Tezze et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tezze et al., 2017

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  • Classified as probably not a substantial claim.

    Premisecitation

    Disrupted mitochondrial dynamics is one of the hallmarks of aging.

    “Disrupted mitochondrial dynamics is one of the hallmarks of aging (Lopez‐Otin, Blasco, Partridge, Serrano, & Kroemer, 2013).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Lopez‐Otin, Blasco, Partridge, Serrano, & Kroemer, 2013

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Regulation of mitochondrial remodeling and associated bioenergetic changes in skeletal muscle is key for correct adaptation and response to exercise that results in increased mitochondrial content with improved fatty acid oxidation and glucose homeostasis.

    “The regulation of mitochondrial remodeling and associated bioenergetic changes, particularly in skeletal muscle, is key for the correct adaptation and response to exercise that results in an increased mitochondrial content with improved fatty acid oxidation and glucose homeostasis (Mansueto et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mansueto et al., 2017

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Up to 30% loss of mitochondrial content has been reported in fast twitch muscles during aging, with accumulation of dysfunctional mitochondria.

    “with up to a 30% loss of mitochondrial content reported in fast twitch muscles and an accumulation of dysfunctional mitochondria (Chabi et al., 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Chabi et al., 2008

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Functional studies have demonstrated that miRs play a key role in regulating expression of genes and pathways altered during exercise and/or aging, contributing to alterations in skeletal muscle mass.

    “Although limited, functional studies have demonstrated that miRs play a key role in regulating the expression of genes and pathways altered during exercise and/or aging, contributing to alterations in skeletal muscle mass (Li, Chan, Yu, & Zhou, 2017; Silva, Bye, el Azzouzi, & Wisløff, 2017; Soares et al., 2014).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Li, Chan, Yu, & Zhou, 2017

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    • cites Silva, Bye, el Azzouzi, & Wisløff, 2017

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    • cites Soares et al., 2014

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The role of miRs in regulation of key cellular mechanisms including skeletal muscle homeostasis, development, regeneration, and atrophy has become increasingly recognized.

    “The role of miRs in the regulation of key cellular mechanisms has become increasingly recognized, including skeletal muscle homeostasis, development, regeneration, and atrophy (Cheung et al., 2012; Goljanek‐Whysall et al., 2011; Soares et al., 2014).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Cheung et al., 2012

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    • cites Goljanek‐Whysall et al., 2011

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    • cites Soares et al., 2014

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Interruption of mitochondrial dynamics can result in mitochondrial swelling, loss of cristae, destruction of the inner membrane, and impaired respiration.

    “Interruption of mitochondrial dynamics can result in mitochondrial swelling, loss of cristae, destruction of the inner membrane, and impaired respiration (Bratic & Larsson, 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bratic & Larsson, 2013

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Mitophagy is regulated at numerous levels, and distinct mitophagic pathways have been elucidated such as ubiquitin-mediated mitophagy including the Pink/Parkin pathway and ubiquitin-independent pathways via mitophagy receptors on the outer mitochondrial membrane (e.g., BNIP3).

    “Mitophagy is regulated at numerous levels, and a number of distinct mitophagic pathways have been elucidated such as ubiquitin‐mediated mitophagy including the Pink/Parkin pathway and ubiquitin independent pathways via mitophagy receptors on the outer mitochondrial membrane (e.g., BNIP3), however, the exact regulatory mechanisms remain to be fully understood (for reviews, see Montava‐Garriga & Gan”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Montava‐Garriga & Ganley, 2019

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    • cites Palikaras, Lionaki, & Tavernarakis, 2018

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Mitochondria are dynamic organelles that exist in a highly interconnected network and continually undergo fusion and fission.

    “Mitochondria are dynamic organelles that exist in a highly interconnected network and are continually undergoing fusion and fission (for review, see Archer, 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Archer, 2013

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Lower levels of miR-181a in muscle are associated with accumulation of its target genes and potentially dysfunctional mitophagy, leading to accumulation of dysfunctional mitochondria.

    “This suggests that lower levels of miR‐181a in muscle are associated with accumulation of its target genes and potentially dysfunctional mitophagy, leading to an accumulation of dysfunctional mitochondria (Figure 6g).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Skeletal muscle from old compared to adult mice has impaired or dysfunctional autophagic response and mitochondrial biogenesis.

    “This suggests impaired or dysfunctional autophagic response and mitochondrial biogenesis in skeletal muscle from old compared to adult mice, and an increase in p62 levels can be associated with an inhibition of autophagy as it is degraded in cells with normal autophagic flux (Figure 2b).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: p62 is degraded in cells with normal autophagic flux, so increased p62 levels indicate inhibition of autophagy.

  • May combine two claims.

    Interpretationown data

    Increase in expression of regulators of Pink1/Parkin-dependent mitophagy during aging and presence of abnormal mitochondria suggests this mitophagy pathway is disrupted or ineffective, resulting in accumulation of abnormal mitochondria.

    “We have detected an increase in the expression of the regulators of Pink1/Parkin‐dependent mitophagy during aging and the presence of abnormal mitochondria, suggesting this mitophagy pathway is disrupted or ineffective, resulting in an accumulation of abnormal mitochondria.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    These data demonstrate microRNA-mediated fine-tuning of mitochondrial turnover and provide proof of principle for potential use of microRNA-based therapeutic approaches for aging-associated disorders such as age-related muscle atrophy.

    “These data demonstrate microRNA‐mediated fine‐tuning of one of the key mechanisms associated with aging, mitochondrial turnover, and provide proof of principle for the potential use of microRNA‐based therapeutic approaches for aging‐associated disorders such as age‐related muscle atrophy.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Mouse aging models and miR-181a manipulation results are relevant to human age-related muscle atrophy and diseases with disrupted mitochondrial dynamics.

  • May combine two claims.

    Interpretationown data

    miR-181a is a key regulator of p62 and Park2, and indirectly regulates Park7/Protein DJ-1 expression and localization.

    “Using bioinformatics and reporter constructs, we have identified miR‐181a as a key regulator of p62 and Park2, and indirectly, regulation of Park7/Protein DJ‐1 expression and localization.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Changes in miR-181a levels and concomitant changes in expression of its targets resulted in altered myofiber size, mitochondrial content, quality and specific muscle force, suggesting miR-181a may be one of key regulatory mechanisms underlying age-related muscle atrophy.

    “Changes in miR‐181a levels and the concomitant changes in the expression of its targets resulted in altered myofiber size, mitochondrial content, and quality and specific muscle force, suggesting miR‐181a may be one of the key regulatory mechanisms underlying age‐related muscle atrophy.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The role of mitophagy and autophagy in skeletal muscle is context-dependent and even small changes in mitochondrial dynamics can have detrimental consequences on muscle mass and function with accumulation of abnormal mitochondria.

    “The role of mitophagy and autophagy in skeletal muscle is context‐dependent and even small changes in mitochondrial dynamics can have detrimental consequences on muscle mass and function with an accumulation of abnormal mitochondria (Carnio et al., 2014; Drake, Wilson, & Yan, 2016).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Carnio et al., 2014

      Not checked in the free run.

    • cites Drake, Wilson, & Yan, 2016

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Functional autophagy and mitophagy are affected by aging and have been associated with changes in mitochondrial dynamics.

    “Functional autophagy and mitophagy are affected by aging and have been associated with changes in mitochondrial dynamics (Carnio et al., 2014; Sebastian et al., 2016).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Carnio et al., 2014

      Not checked in the free run.

    • cites Sebastian et al., 2016

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    miR-181a increased mitochondrial turnover via mitophagy and potentially concomitant increase in mitochondrial biogenesis as indicated by increase of Tfam expression in C2C12 cells treated with miR-181.

    “These results indicate that miR‐181a increased mitochondrial turnover via mitophagy and potentially concomitant increase in mitochondrial biogenesis as indicated by increase of Tfam expression in C2C12 cells treated with miR‐181.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Mitochondrial content decreases with age in skeletal muscle; however, the exact mechanisms are not fully understood.

    “Mitochondrial content decreases with age in skeletal muscle; however, the exact mechanisms are not fully understood (Hepple, 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Hepple, 2014

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Elevated expression of mitophagy-associated proteins in old TA coupled with decreased miR-181a suggests miR-181a may act as an important regulator of autophagy and mitochondrial dynamics during muscle aging.

    “The elevated expression of mitophagy‐associated proteins observed in TA from old mice coupled with a decreased expression of miR‐181a suggested that miR‐181a may act as an important regulator of autophagy and mitochondrial dynamics during muscle aging.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    p62 and Park2 are direct targets of miR-181a, whereas DJ-1 expression may be regulated by miR-181a in an indirect manner.

    “This confirms p62 and Park2 as direct, targets of miR‐181a, whereas DJ‐1 expression may be regulated by miR‐181a in an indirect manner (Figure 4c,d).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The effects of miR-181a overexpression on mitochondrial dynamics in other tissues were not examined.

    “but the effects on mitochondrial dynamics in other tissues were not examined.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Ponceau S staining was used to ensure equivalent loading.

    “membranes were stained with Ponceau S to ensure equivalent loading.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several microRNAs, including miR-149, miR-761, and miR-494, can inhibit or promote mitochondrial biogenesis.

    “Several microRNAs, including miR‐149, miR‐761, and miR‐494, have been identified that can inhibit or promote mitochondrial biogenesis (Mohamed, Hajira, Pardo, & Boriek, 2014; Xu, Zhao, Sun, Liu, & Zhang, 2015; Yamamoto et al., 2012) for review (Dahlmans, Houzelle, Schrauwen, & Hoeks, 2016).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Mohamed, Hajira, Pardo, & Boriek, 2014

      Not checked in the free run.

    • cites Xu, Zhao, Sun, Liu, & Zhang, 2015

      Not checked in the free run.

    • cites Yamamoto et al., 2012

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Mitophagy is coordinated by a number of conserved cellular pathways, and disruption of this balance can result in the accumulation of dysfunctional mitochondria and aging.

    “Moreover, mitophagy is coordinated by a number of conserved cellular pathways, and disruption of this balance can result in the accumulation of dysfunctional mitochondria and aging (Palikaras et al., 2018).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Palikaras et al., 2018

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Activation of SKN-1 triggers a bipartite retrograde signaling pathway coupling the induction of mitochondrial biogenesis and mitophagy genes.

    “Activation of SKN‐1 triggered a bipartite retrograde signaling pathway coupling the induction of mitochondrial biogenesis and mitophagy genes (Palikaras et al., 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Palikaras et al., 2015

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Only male mice were analyzed in this study.

    “We also only analyzed male mice in this study”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In C. elegans, the age-related decline in mitophagy inhibits the removal of dysfunctional mitochondria and impairs mitochondrial biogenesis.

    “In C. elegans, the age‐related decline in mitophagy inhibits both the removal of dysfunctional mitochondria and impairs mitochondrial biogenesis (Palikaras, Lionaki, & Tavernarakis, 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Palikaras, Lionaki, & Tavernarakis, 2015

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    During myogenic differentiation of C2C12 myoblasts, mitophagy is induced with a corresponding increase in mitochondrial biogenesis.

    “It has also been demonstrated that during the myogenic differentiation of C2C12 myoblasts, there is an induction of mitophagy with a corresponding increase in mitochondrial biogenesis (Sin et al., 2016).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sin et al., 2016

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Overexpression of miR-181a/b-1 in chondrocytes resulted in improvements in mitochondrial metabolism.

    “Recently, overexpression of miR‐181a/b‐1 in chondrocytes resulted in improvements in mitochondrial metabolism (Zheng, Liu, Tycksen, Nunley, & McAlinden, 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Zheng, Liu, Tycksen, Nunley, & McAlinden, 2019

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Mitochondrial biogenesis was measured indirectly using microscopy and expression levels of PGC1α, Tfam, Nd-1, and Cox-1.

    “Similarly, we used microscopy and the expression levels of PGC1α, Tfam, and mitochondrial encoded genes Nd‐1 and Cox‐1 as indirect measures of mitochondrial biogenesis in our models.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Inducible muscle-specific deletion of DRP1 resulted in formation of functionally abnormally large mitochondria, activation of ER stress response, increase in Ca2+ uptake and myofibre death.

    “Similarly, inducible muscle‐specific deletion of the mitochondrial fission protein, DRP1, resulted in the formation of functionally abnormally large mitochondria, activation of the ER stress response, an increase in Ca2+ uptake and myofibre death (Favaro et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Favaro et al., 2019

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inducible muscle-specific deletion of both OPA1 and DRP1 rescued the lethal phenotype of OPA1 knockout, suggesting in the context of mitochondrial dynamics inhibition of fission has precedence over inhibition of fusion.

    “Interestingly, inducible muscle‐specific deletion of both OPA1 and DRP1 rescued the lethal phenotype of OPA1 knockout, suggesting that in the context of mitochondrial dynamics inhibition of fission has precedence over inhibition of fusion (Romanello et al., 2019).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Romanello et al., 2019

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mitophagy and mitochondrial biogenesis are coupled.

    “Mitophagy and mitochondrial biogenesis have been demonstrated to be coupled previously (Palikaras et al., 2015; Sin et al., 2016).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Palikaras et al., 2015

      Not checked in the free run.

    • cites Sin et al., 2016

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Fine-tuning the levels of autophagy regulatory (p62) and mitophagy-associated proteins (DJ-1, Park2) and concomitant changes in the expression of Tfam, by overexpressing miR-181a, leads to improved mitochondrial dynamics resulting in increased myofiber size and muscle function.

    “We have demonstrated that fine‐tuning the levels of autophagy regulatory (p62) and mitophagy‐associated proteins (DJ‐1, Park2) and concomitant changes in the expression of Tfam, by overexpressing miR‐181a, leads to improved mitochondrial dynamics resulting in increased myofiber size and muscle function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Increased expression of miR-181a in response to acute exercise suggests that miR-181a plays a key role in improving overall mitochondrial health.

    “the increased expression of miR‐181a in response to acute exercise (this study and (Safdar, Abadi, Akhtar, Hettinga, & Tarnopolsky, 2009) suggests that miR‐181a plays a key role in improving overall mitochondrial health.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Safdar, Abadi, Akhtar, Hettinga, & Tarnopolsky, 2009

      Not checked in the free run.

    • Rests on an assumption: Exercise increases mitochondrial biogenesis in skeletal muscle.

  • May combine two claims.

    Interpretationown data

    miR-181a regulates mitochondrial dynamics by fine-tuning the Pink/Park pathway and mitochondrial biogenesis, potentially in response to stress factors.

    “Our data suggest that miR‐181a regulates mitochondrial dynamics by fine‐tuning the Pink/Park pathway and mitochondrial biogenesis, potentially in response to stress factors.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    miR-181a-mediated regulation of components of autophagy has been reported in aging, cancer cell lines, and nervous system.

    “miR‐181a‐mediated regulation of components of autophagy has previously been reported in aging, cancer cell lines, and nervous system (Cheng et al., 2016; Indrieri et al., 2019; Rippo et al., 2014; Soriano‐Arroquia, House, Tregilgas, Canty‐Laird, & Goljanek‐Whysall, 2016; Tekirdag, Korkmaz, Ozturk, Agami, & Gozuacik, 2013).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Cheng et al., 2016

      Not checked in the free run.

    • cites Indrieri et al., 2019

      Not checked in the free run.

    • cites Rippo et al., 2014

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Overexpression of miR-181a increases the expression of genes required for mitochondrial biogenesis and promotes mitophagy either directly or indirectly to restore mitochondrial dynamics.

    “Our results indicate overexpression of miR‐181a increases the expression of genes required for mitochondrial biogenesis and promotes mitophagy either directly or indirectly to restore mitochondrial dynamics.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Dysregulated mitophagy is associated with decreased functional mitochondria in muscle during aging, where changes in mitochondrial fusion or fission may lead to presence of abnormally large mitochondria.

    “Dysregulated mitophagy is associated with decreased functional mitochondria in muscle during aging, where changes in mitochondrial fusion or fission may lead to the presence of abnormally large mitochondria (Mao & Klionsky, 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Mao & Klionsky, 2013

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Each experiment was carried out using at least two independent plasmid preparations in triplicates.

    “Each experiment was carried out using at least two independent plasmid preparations in triplicates.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In mice, deletion of OPA1 produced a lethal phenotype, while inducible muscle-specific deletion of OPA1 resulted in disruption of mitochondrial morphology, proteasome activation, and muscle atrophy.

    “In mice, the deletion of the mitochondrial fusion protein, OPA1, produced a lethal phenotype, while inducible muscle‐specific deletion of OPA1 resulted in a disruption of mitochondrial morphology, proteasome activation, and muscle atrophy (Tezze et al., 2017).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tezze et al., 2017

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Blinded observers counted minimal Feret's diameter in transverse sections.

    “Transverse sections from 3 to 4 muscles/treatment group were examined by blinded observers to count the minimal Feret's diameter.”
    Quote in the paperNot a substantial claim
79 of 79

  • The paper relies on this without support.

    p62 is degraded in cells with normal autophagic flux, so increased p62 levels indicate inhibition of autophagy.

    “an increase in p62 levels can be associated with an inhibition of autophagy as it is degraded in cells with normal autophagic flux (Figure 2b).”

  • The paper relies on this without support.

    The C2C12 myoblast model and in vitro manipulations reflect skeletal muscle mitochondrial dynamics in vivo.

    “In vitro experiments confirmed miR‐181a targets p62 and Park2, and demonstrated that miR‐181a regulates mitophagic flux.”

  • The paper relies on this without support.

    Mouse aging models and miR-181a manipulation results are relevant to human age-related muscle atrophy and diseases with disrupted mitochondrial dynamics.

    “These results provide physiological evidence for the potential of microRNA‐based interventions for age‐related muscle atrophy and of wider significance for diseases with disrupted mitochondrial dynamics.”

  • The paper relies on this without support.

    microRNAs fine-tune gene expression.

    “As miRs have been shown to fine‐tune gene expression”

  • The paper relies on this without support.

    Exercise increases mitochondrial biogenesis in skeletal muscle.

    “Exercise increases mitochondrial biogenesis in skeletal muscle”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Mitophagy-related proteins are decreased in the skeletal muscle of old rodents, although conflicting data exist.

    “Although conflicting data exist [54,145,146,147], several studies reported that mitophagy-related proteins are decreased in the skeletal muscle of old rodents [46,120,148,149,150,151,152].”

    From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [145]

  • In the majority of studies that reported an increase in Parkin content in aged muscles, mitophagy was also reported to be impaired or insufficient in aged skeletal muscles.

    “Importantly, the majority of studies that reported an increase in Parkin content in aged muscles also reported that mitophagy was impaired/insufficient in aged skeletal muscles [145,146,147].”

    From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [145]

  • Injecting old mice with a miR-181a mimic resulted in improved skeletal muscle force, increased myofiber size, and a trend for increased succinate dehydrogenase activity.

    “Recently, it was shown that injecting old mice with a miR-181a mimic (miR-181a being a microRNA known to enhance mitophagy in myoblasts) resulted in improved skeletal muscle force, increased myofiber size, and a trend for increased succinate dehydrogenase activity [145].”

    From Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging (2021) · cites this paper as [145]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Acute exercise is reported to both decrease and increase miR‐181a

    Minor

    The results state that exercise downregulated miR‐181a in adult mice, while the discussion states that acute exercise increased it.

1 of 1

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Authors
Goljanek‐Whysall, K., Soriano‐Arroquia, A., McCormick, R., Chinda, C., & McDonagh, B.
Affiliations
  • University of Liverpool (GB)
  • Ollscoil na Gaillimhe – University of Galway (IE)
Corresponding author
  • Goljanek‐Whysall, Katarzyna
  • McDonagh, Brian
ORCID
Venue
Aging Cell
Publisher
Wiley
Published
2020-04
Volume
19
Issue
4
Pages
e13140-e13140
ISSN
  • 1474-9718 (ISSN-L)
  • 1474-9726
DOI
10.1111/acel.13140
PMC
PMC7189996
OpenAlex
W3015732281
Cited by
81
References
56
Citations by year
2026: 4 · 2025: 11 · 2024: 17 · 2023: 14 · 2022: 10 · 2021: 16 · 2020: 9
FWCI
3.97
Type
journal article
Language
en
Open access
Licence
Locations
  • Aging Cell (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Lenus, The Irish Health Repository (Dr Steevens Hospital Library) (submittedVersion)
Funders
  • Biotechnology and Biological Sciences Research Council (BB/L021668/1)
  • Irish Research Council (IRCLA/2017/101)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
miR-181a, mitochondrial dynamics, skeletal muscle aging, p62, Parkin, DJ-1, autophagy, mitochondrial quality control, age-related muscle loss, microRNA regulation, muscle function
MeSH terms
Sequestosome-1 Protein, Protein Deglycase DJ-1, Animals, Cells, Cultured, Mice, Inbred C57BL, Mitochondria, Cellular Senescence, Muscle, Skeletal, MicroRNAs, Proteomics, Ubiquitin-Protein Ligases, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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