Atrogin-1/MAFbx and MuRF1 Are Downregulated in Aging-Related Loss of Skeletal Muscle

Edström, Erik; Altun, Mikael; Hägglund, Martin; Ulfhake, Brun

doi:10.1093/gerona/61.7.663

Cited by 170 publications

(139 citation statements)

References 73 publications

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“…52 These studies suggest that the association between Atrogin-1 and muscle atrophy may be fiber type-or gender-dependent. Another explanation could be that sarcopenia is mechanistically different from acute muscle atrophy, which is marked by increased expression of Atrogin-1, as suggested by Edstrom et al 51 This statement is supported by the findings of Giresi and colleagues, 45 who conducted a microarray study with muscle samples from 19-25-yr-old and 70-80-yr-old male subjects to identify the molecular signature of sarcopenia.…”

Section: Discussionmentioning

confidence: 71%

“…In experimental animal studies, Atrogin-1 has been shown to be highly expressed in skeletal muscles which were atrophying due to fasting or diverse diseases. 36,37 In very recent studies, downregulation of ATROGIN-1 in sarcopenic, slow-twitch muscles of aged, female rats was demonstrated 51 whereas opposite results were obtained in fasttwitch muscles of aged, male rats. 52 These studies suggest that the association between Atrogin-1 and muscle atrophy may be fiber type-or gender-dependent.…”

Section: Discussionmentioning

confidence: 99%

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Muscular Transcriptome in Postmenopausal Women With or Without Hormone Replacement

Pöllänen

Ronkainen

Suominen

et al. 2007

Rejuvenation Research

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The loss of muscle mass and strength with aging is well characterized, but our knowledge of the molecular mechanisms underlying the development of sarcopenia remains incomplete. Although menopause is often accompanied with first signs of age-associated changes in muscle structure and function, the effects of hormone replacement therapy (HRT) or menopause-related decline in estrogen production in the muscles of postmenopausal women is not well understood.Furthermore the knowledge of the global transcriptional changes that take place in skeletal muscle in relation to estrogen status has thus far been completely lacking. We used a randomized double-blinded study design together with an explorative microarray experiment to characterize possible effects of continuous, combined HRT and estrogen deprivation on the skeletal muscle of fifteen women. Here, we report the differential response of both GO-annotated biological processes and some individual genes responding differentially to the use or non-use of HRT. Our results revealed transcription level changes in, e.g., muscle protein and energy metabolism. In particular, the ubiquitine-proteosome system was found to be effected at several levels. HRT seemed to partially counteract the postmenopause-related transcriptional changes. Our results suggest that during the early postmenopausal years, when there is no counteracting medication available, muscle transcriptome changes notably, whereas HRT appears to slow-down this phenomenon and could therefore aid in maintaining proper muscle mass and function after menopause.3

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Muscular Transcriptome in Postmenopausal Women With or Without Hormone Replacement

Pöllänen

Ronkainen

Suominen

et al. 2007

Rejuvenation Research

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show abstract

“…In contrast, in the aged muscles, mRNAs for Atrogin-1/MAFbx, MuRF1, and the Ub-conjugating enzyme, E2-14K, were unchanged or lower than adult levels (Fig. 7A) (36). Also, treatment with the glucocorticoid, dexamethasone (Fig.…”

Section: Discussionmentioning

confidence: 87%

Muscle Wasting in Aged, Sarcopenic Rats Is Associated with Enhanced Activity of the Ubiquitin Proteasome Pathway

Altun

Besche

Overkleeft

et al. 2010

Journal of Biological Chemistry

190

155

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Among the hallmarks of aged organisms are an accumulation of misfolded proteins and a reduction in skeletal muscle mass ("sarcopenia"). We have examined the effects of aging and dietary restriction (which retards many age-related changes) on components of the ubiquitin proteasome system (UPS) in muscle. The hindlimb muscles of aged (30 months old) rats showed a marked loss of muscle mass and contained 2-3-fold higher levels of 26S proteasomes than those of adult (4 months old) controls. 26S proteasomes purified from muscles of aged and adult rats showed a similar capacity to degrade peptides, proteins, and an ubiquitylated substrate, but differed in levels of proteasome-associated proteins (e.g. the ubiquitin ligase E6AP and deubiquitylating enzyme USP14). Also, the activities of many other deubiquitylating enzymes were greatly enhanced in the aged muscles. Nevertheless, their content of polyubiquitylated proteins was higher than in adult animals. The aged muscles contained higher levels of the ubiquitin ligase CHIP, involved in eliminating misfolded proteins, and MuRF1, which ubiquitylates myofibrillar proteins. These muscles differed from ones rapidly atrophying due to disease, fasting, or disuse in that Atrogin-1/MAFbx expression was low and not inducible by glucocorticoids. Thus, the muscles of aged rats showed many adaptations indicating enhanced proteolysis by the UPS, which may enhance their capacity to eliminate misfolded proteins and seems to contribute to the sarcopenia. Accordingly, dietary restriction decreased or prevented the aging-associated increases in proteasomes and other UPS components and reduced muscle wasting.

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“…In addition, it has been shown that atrogin-1/MAFbx and MuRF1 are down-regulated as a result of AKT (protein kinase B)-mediated inactivation of Foxo4. This activation of AKT was shown to be mediated through the insulin-like growth factor-1 (IGF-1) receptor signalling [14]. Finally, it has been shown that activation of AMPK stimulates myofibrillar protein degradation through the expression of atrogin-1/MAFbx and MuRF1 by increasing Foxo transcription factors in skeletal muscles [15].…”

Section: Discussionmentioning

confidence: 99%

“…AMPK has been shown to enhance muscle protein degradation through promoting the expression of two muscle-specific ubiquitin ligases, MAFbx and MuRF1 [17]. Muscle atrophy in many conditions share a common mechanism in the up-regulation of MAFbx and MuRF1, both of which are part of the ubiquitin proteasome pathway utilized for protein degradation during muscle atrophy [14].…”

Section: Discussionmentioning

confidence: 99%

Insulin down-regulates the expression of ubiquitin E3 ligases partially by inhibiting the activity and expression of AMP-activated protein kinase in L6 myotubes

et al. 2015

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SynopsisWhile insulin is an anabolic hormone, AMP-activated protein kinase (AMPK) is not only a key energy regulator, but it can also control substrate metabolism directly by inducing skeletal muscle protein degradation. The hypothesis of the present study was that insulin inhibits AMPK and thus down-regulates the expression of the ubiquitin E3 ligases, muscle atrophy F-box (MAFbx) and muscle RING finger 1 (MuRF1) in skeletal muscle cells. Differentiated L6 myotubes were treated with 5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR) and/or compound C to stimulate and/or block AMPK respectively. These treatments were also conducted in the presence or absence of insulin and the cells were analysed by western blot and quantitative real-time PCR. In addition, nuleotide levels were determined using HPLC. The activation of AMPK with AICAR enhanced the mRNA levels of MAFbx and MuRF1. Insulin reduced the phosphorylation and activity AMPK, which was accompanied by reduced MAFbx and MuRF1 mRNA levels. Using a protein kinase B (PKB/Akt) inhibitor, we found that insulin regulates AMPK through the activation of Akt. Furthermore, insulin down-regulated AMPK α2 mRNA. We conclude that insulin inhibits AMPK through Akt phosphorylation in L6 myotubes, which may serve as a possible signalling pathway for the down-regulation of protein degradation. In addition, decreased expression of AMPK α2 may partially participate in inhibiting the activity of AMPK.

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Atrogin-1/MAFbx and MuRF1 Are Downregulated in Aging-Related Loss of Skeletal Muscle

Cited by 170 publications

References 73 publications

Muscular Transcriptome in Postmenopausal Women With or Without Hormone Replacement

Muscular Transcriptome in Postmenopausal Women With or Without Hormone Replacement

Muscle Wasting in Aged, Sarcopenic Rats Is Associated with Enhanced Activity of the Ubiquitin Proteasome Pathway

Insulin down-regulates the expression of ubiquitin E3 ligases partially by inhibiting the activity and expression of AMP-activated protein kinase in L6 myotubes

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