Activation of an alternative
            <scp>NF‐ΚB</scp>
            pathway in skeletal muscle during disuse atrophy

Hunter, R. Bridge; Stevenson, Eric J.; Koncarevic, Alan; Mitchell-Felton, Heather; Essig, David A.; Kandarian, Susan C.

doi:10.1096/fj.01-0866com

Cited by 254 publications

(271 citation statements)

References 68 publications

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“…Data from our lab [17,19] and others [45] have consistently shown an increase in the protein content for Bcl-2 following disuse and in aged muscles, with further increases when disuse is superimposed with aging. This led to our hypothesis that aged muscles attempt to counteract pro-apoptotic stimuli by up-regulating anti-apoptotic proteins.…”

Section: Apoptotic Changes In Aged Skeletal Musclesupporting

confidence: 55%

Death receptor-associated pro-apoptotic signaling in aged skeletal muscle

2006

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Tumor necrosis factor-alpha (TNF-α) is elevated in the serum as a result of aging and it promotes pro-apoptotic signaling upon binding to the type I TNF receptor. It is not known if activation of this apoptotic pathway contributes to the well-documented age-associated decline in muscle mass (i.e. sarcopenia). We tested the hypothesis that skeletal muscles from aged rodents would exhibit elevations in markers involved in the extrinsic apoptotic pathway when compared to muscles from young adult rodents, thereby contributing to an increased incidence of nuclear apoptosis in these muscles. The plantaris (fast) and soleus (slow) muscles were studied in young adult (5-7 mo, n = 8) and aged (33 mo, n = 8) Fischer 344 × Brown Norway rats. Muscles from aged rats were significantly smaller while exhibiting a greater incidence of apoptosis. Furthermore, muscles from aged rats had higher type I TNF receptor and Fas associated death domain protein (FADD) mRNA, protein contents for FADD, BCL-2 Interacting Domain (Bid), FLICE-inhibitory protein (FLIP), and enzymatic activities of caspase-8 and caspase-3 than muscles from young adult rats. Significant correlations were observed in the plantaris muscle between caspase activity and muscle weight and the apoptotic index, while similar relationships were not found in the soleus. These data demonstrate that pro-apoptotic signaling downstream of the TNF receptor is active in aged muscles. Furthermore, our data extend the previous demonstration that type II fibers are preferentially affected by aging and support the hypothesis that type II fiber containing skeletal muscles may be more susceptible to muscle mass loses via the extrinsic apoptotic pathway.

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Section: Apoptotic Changes In Aged Skeletal Musclesupporting

confidence: 55%

Death receptor-associated pro-apoptotic signaling in aged skeletal muscle

2006

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“…There are few studies which have looked at NF-kB activation in skeletal muscle under conditions of muscle wasting. However, a recent study (Hunter et al, 2002) showed nuclear extracts from the soleus muscle of rats undergoing disuse atrophy to show increased binding of NF-kB oligonucleotides. This complex bound antibody to p50, c-Rel and Bcl-3, but not other NF-kB members, and there was no evidence for the canonical NFkB pathway involving activation of p65 or I-kBa.…”

Section: Discussionmentioning

confidence: 97%

NF-κB mediates proteolysis-inducing factor induced protein degradation and expression of the ubiquitin–proteasome system in skeletal muscle

2005

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Loss of skeletal muscle in cancer cachexia has a negative effect on both morbidity and mortality. The role of nuclear factor-kB (NFkB) in regulating muscle protein degradation and expression of the ubiquitin -proteasome proteolytic pathway in response to a tumour cachectic factor, proteolysis-inducing factor (PIF), has been studied by creating stable, transdominant-negative, muscle cell lines. Murine C 2 C 12 myoblasts were transfected with plasmids with a CMV promoter that had mutations at the serine phosphorylation sites required for degradation of I-kBa, an NF-kB inhibitory protein, and allowed to differentiate into myotubes. Proteolysis-inducing factor induced degradation of I-kBa, nuclear accumulation of NF-kB and an increase in luciferase reporter gene activity in myotubes containing wild-type, but not mutant, I-kBa proteins. Proteolysis-inducing factor also induced total protein degradation and loss of the myofibrillar protein myosin in myotubes containing wild-type, but not mutant, plasmids at the same concentrations as those causing activation of NF-kB. Proteolysis-inducing factor also induced increased expression of the ubiquitinproteasome pathway, as determined by 'chymotrypsin-like' enzyme activity, the predominant proteolytic activity of the b-subunits of the proteasome, protein expression of 20S a-subunits and the 19S subunits MSS1 and p42, as well as the ubiquitin conjugating enzyme, E2 14k , in cells containing wild-type, but not mutant, I-kBa. The ability of mutant I-kBa to inhibit PIF-induced protein degradation, as well as expression of the ubiquitin -proteasome pathway, confirms that both of these responses depend on initiation of transcription by NF-kB.

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“…Nuclear factor-kB may also be involved in other conditions of muscle wasting. Thus, hind-limb unloading, a model of disuse atrophy, resulted in a 10-fold increase in the activity of a transfected NF-kB-dependent reporter (Hunter et al, 2002), but this involved p50, c-Rel and Bcl-3 and not activation of p65 or I-kB, and is thus distinct from cachexia. This suggests that inhibitors of the release and subsequent nuclear translocation of NF-kB, or the binding of NF-kB to DNA should be evaluated as potential agents to prevent muscle atrophy in cancer cachexia.…”

Section: Discussionmentioning

confidence: 97%

Induction of proteasome expression in skeletal muscle is attenuated by inhibitors of NF-κB activation

2004

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The potential for inhibitors of nuclear factor-kB (NF-kB) activation to act as inhibitors of muscle protein degradation in cancer cachexia has been evaluated both in vitro and in vivo. Activation of NF-kB is important in the induction of proteasome expression and protein degradation by the tumour factor, proteolysis-inducing factor (PIF), since the cell permeable NF-kB inhibitor SN50 (18 mM) attenuated the expression of 20S proteasome a-subunits, two subunits of the 19S regulator MSS1 and p42, and the ubiquitinconjugating enzyme, E2 14k , as well as the decrease in myosin expression in murine myotubes. To assess the potential therapeutic benefit of NF-kB inhibitors on muscle atrophy in cancer cachexia, two potential inhibitors were employed; curcumin (50 mM) and resveratrol (30 mM). Both agents completely attenuated total protein degradation in murine myotubes at all concentrations of PIF, and attenuated the PIF-induced increase in expression of the ubiquitin -proteasome proteolytic pathway, as determined by the 'chymotrypsin-like' enzyme activity, proteasome subunits and E2 14k . However, curcumin (150 and 300 mg kg À1 ) was ineffective in preventing weight loss and muscle protein degradation in mice bearing the MAC16 tumour, whereas resveratrol (1 mg kg À1 ) significantly attenuated weight loss and protein degradation in skeletal muscle, and produced a significant reduction in NF-kB DNAbinding activity. The inactivity of curcumin was probably due to a low bioavailability. These results suggest that agents which inhibit nuclear translocation of NF-kB may prove useful for the treatment of muscle wasting in cancer cachexia.

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Activation of an alternative NF‐ΚB pathway in skeletal muscle during disuse atrophy

Cited by 254 publications

References 68 publications

Death receptor-associated pro-apoptotic signaling in aged skeletal muscle

Death receptor-associated pro-apoptotic signaling in aged skeletal muscle

NF-κB mediates proteolysis-inducing factor induced protein degradation and expression of the ubiquitin–proteasome system in skeletal muscle

Induction of proteasome expression in skeletal muscle is attenuated by inhibitors of NF-κB activation

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