Altered proteasome function and subunit composition in aged muscle

Husom, Aimee D.; Peters, Elizabeth A.; Kolling, Erin A.; Fugere, Nicole A.; Thompson, La Dora V.; Ferrington, Deborah A.

doi:10.1016/j.abb.2003.10.010

Cited by 181 publications

(172 citation statements)

References 65 publications

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“…First, while the general consensus has been that proteasome content and function declines with age (reviewed in Carrard et al, 2002;Gaczynska et al, 2001), this phenomenon is not universal as effects appear to be tissue-specific. For example, in contrast with the general decline in content reported in many tissues, we have previously reported a threefold increase in proteasome content in aged rat muscle (Ferrington et al, 2005;Husom et al, 2004). Additionally, aging can differentially affect tissues in close proximity, as has been shown comparing regions of the brain (Mishto et al, 2006;Zeng et al, 2005) and in the present study for the retina.…”

Section: Discussion Altered Proteasome Function With Agingcontrasting

confidence: 78%

“…Total proteasome content was determined from the immune reactions of the α6 or α7 subunits of the 20S core. The α-subunits are part of the constitutive complex and therefore, provide a valid estimate of the total content (Ferrington et al, 2005;Husom et al, 2004). Densitometric analysis of the immunoreaction revealed no age-dependent change in proteasome content in both the retina ( Figure 2A) and RPE ( Figure 2B).…”

Section: Analysis Of Proteasome Content and Subunit Compositionmentioning

confidence: 96%

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Age-dependent inhibition of proteasome chymotrypsin-like activity in the retina

Kapphahn

Bigelow

Ferrington

2007

Experimental Eye Research

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The proteasome plays a fundamental role in processes essential for cell viability. A loss in proteasome function has been associated with aging, as well as a number of age-related diseases. Defining the mechanism(s) behind this loss in function will add important information regarding the molecular basis for aging. In the current study, we performed an age-based comparison of proteasome function and composition of subunits and regulatory proteins in the neural retina and retinal pigment epithelium (RPE) in Fischer 344 rats. In the RPE, there was no age-dependent difference in activity, subunit composition, or content of proteasome regulators, PA28 and PA700. In contrast, the aged neural retina demonstrated a significant reduction in the chymotrypsin-like activity and decreased degradation of both casein and casein modified by 4-hydroxynonenal. This loss in function could not be explained by differences in subunit composition, content of PA28 and PA700, or reversible modification of cysteine residues. To begin investigating the molecular basis for the age-associated decrement in proteasome function, we modified the cysteine residues in proteasome from young rats with the sulfhydryl reactive chemical N-ethylmaleimide. We observed inhibition of the chymotrypsin-like activity and decreased degradation of casein that was comparable to that seen in aged retinas. Thus, chemical modification of cysteine provides an in vitro method that partially recapitulates aging proteasome. Further studies are required to confirm irreversible modification of functionally significant cysteine as a potential mechanism behind the age-related loss in proteasome function.

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Section: Discussion Altered Proteasome Function With Agingcontrasting

confidence: 78%

Section: Analysis Of Proteasome Content and Subunit Compositionmentioning

confidence: 96%

Age-dependent inhibition of proteasome chymotrypsin-like activity in the retina

Kapphahn

Bigelow

Ferrington

2007

Experimental Eye Research

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“…While both proteasome activity and the E3 ligases that mark proteins for degradation are upregulated during muscle atrophy, data on the ubiquitin proteasome system and age‐related muscle atrophy vary widely; increased, decreased, and no change in proteasome activity have been reported in aged rodents (Radák et al ., 2002; Husom et al ., 2004; Wenz et al ., 2009). We found no change in proteasome activity or myogenin‐regulated E3 ligases in old mice compared with young.…”

Section: Discussionmentioning

confidence: 99%

The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging

Walsh¹,

et al. 2015

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SummarySarcopenia, the loss of skeletal muscle mass and function during aging, is a major contributor to disability and frailty in the elderly. Previous studies found a protective effect of reduced histone deacetylase activity in models of neurogenic muscle atrophy. Because loss of muscle mass during aging is associated with loss of motor neuron innervation, we investigated the potential for the histone deacetylase (HDAC) inhibitor butyrate to modulate age‐related muscle loss. Consistent with previous studies, we found significant loss of hindlimb muscle mass in 26‐month‐old C57Bl/6 female mice fed a control diet. Butyrate treatment starting at 16 months of age wholly or partially protected against muscle atrophy in hindlimb muscles. Butyrate increased muscle fiber cross‐sectional area and prevented intramuscular fat accumulation in the old mice. In addition to the protective effect on muscle mass, butyrate reduced fat mass and improved glucose metabolism in 26‐month‐old mice as determined by a glucose tolerance test. Furthermore, butyrate increased markers of mitochondrial biogenesis in skeletal muscle and whole‐body oxygen consumption without affecting activity. The increase in mass in butyrate‐treated mice was not due to reduced ubiquitin‐mediated proteasomal degradation. However, butyrate reduced markers of oxidative stress and apoptosis and altered antioxidant enzyme activity. Our data is the first to show a beneficial effect of butyrate on muscle mass during aging and suggests HDACs contribute to age‐related muscle atrophy and may be effective targets for intervention in sarcopenia and age‐related metabolic disease.

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“…As mentioned, FOXOs are involved in the proteasome system degradation of short‐lived and regulatory cytosolic proteins. Aging is associated with a decreased proteasomal activity, leading to excess of damaged proteins in muscle, liver, and heart (Conconi et al ., 1996; Petropoulos et al ., 2000; Bulteau et al ., 2002; Husom et al ., 2004). Moreover, pathogenesis of neurodegenerative disorders such as Parkinson's, Alzheimer's, or Huntington's disease is generally related to an abnormal ubiquitin‐proteasome mechanism as either a primary cause or secondary consequence (Ciechanover & Brundin, 2003; Kikis et al ., 2010; Webb & Brunet, 2014).…”

Section: Foxo and Autophagymentioning

confidence: 99%

“…Aging is associated with a decreased proteasomal activity, leading to excess of damaged proteins in muscle, liver, and heart (Conconi et al ., 1996; Petropoulos et al ., 2000; Bulteau et al ., 2002; Husom et al ., 2004). Foxo3 has been shown to be a transcriptional regulator of muscle‐specific E3 ubiquitin ligases, which are major effectors of protein degradation in muscle (Sandri et al ., 2004, 2006; Stitt et al ., 2004).…”

Section: Animal Modelsmentioning

confidence: 99%

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

2015

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SummaryAging constitutes the key risk factor for age‐related diseases such as cancer and cardiovascular and neurodegenerative disorders. Human longevity and healthy aging are complex phenotypes influenced by both environmental and genetic factors. The fact that genetic contribution to lifespan strongly increases with greater age provides basis for research on which “protective genes” are carried by long‐lived individuals. Studies have consistently revealed FOXO (Forkhead box O) transcription factors as important determinants in aging and longevity. FOXO proteins represent a subfamily of transcription factors conserved from Caenorhabditis elegans to mammals that act as key regulators of longevity downstream of insulin and insulin‐like growth factor signaling. Invertebrate genomes have one FOXO gene, while mammals have four FOXO genes: FOXO1, FOXO3, FOXO4, and FOXO6. In mammals, this subfamily is involved in a wide range of crucial cellular processes regulating stress resistance, metabolism, cell cycle arrest, and apoptosis. Their role in longevity determination is complex and remains to be fully elucidated. Throughout this review, the mechanisms by which FOXO factors contribute to longevity will be discussed in diverse animal models, from Hydra to mammals. Moreover, compelling evidence of FOXOs as contributors for extreme longevity and health span in humans will be addressed.

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Altered proteasome function and subunit composition in aged muscle

Cited by 181 publications

References 65 publications

Age-dependent inhibition of proteasome chymotrypsin-like activity in the retina

Age-dependent inhibition of proteasome chymotrypsin-like activity in the retina

The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

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