Evidence that lysosomes are not involved in the degradation of myofibrillar proteins in rat skeletal muscle

Lowell, Bradford B.; Ruderman, Neil B.; Goodman, M. N.

doi:10.1042/bj2340237

Cited by 213 publications

(132 citation statements)

References 21 publications

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“…Of the three, the latter is considered to be most important (Lecker et al, 1999), since the former two processes contribute less than 15 -20% of total protein breakdown and do not catabolise myofibrillar proteins (Lowell et al, 1986). In cancer cachexia, where there is extensive and specific loss of skeletal muscle, tissue levels of mRNA for ubiquitin, 20S proteasome a and b subunits and the ubiquitin-conjugating enzyme, E2 14k , have been found to be increased in mouse (Lorite et al, 1998), rat (Temparis et al, 1994) and humans (Williams et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Induction of protein catabolism in myotubes by 15(S)-hydroxyeicosatetraenoic acid through increased expression of the ubiquitin–proteasome pathway

2003

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The potential role of 15(S)-hydroxyeicosatetraenoic acid (15(S)-HETE) as an intracellular signal for increased protein catabolism and induction of the expression of key components of the ubiquitin -proteasome proteolytic pathway induced by a tumour cachectic factor, proteolysis-inducing factor has been studied in murine C 2 C 12 myotubes. 15(S)-HETE induced protein degradation in these cells with a maximal effect at concentrations between 78 and 312 nM. The effect was attenuated by the polyunsaturated fatty acid, eicosapentaenoic acid (EPA). There was an increase in 'chymotrypsin-like' enzyme activity, the predominant proteolytic activity of the proteasome, in the same concentration range as that inducing total protein degradation, and this effect was also attenuated by EPA. 15(S)-hydroxyeicosatetraenoic acid also increased maximal expression of mRNA for proteasome subunits C2 and C5, as well as the ubiquitin-conjugating enzyme, E2 14k , after 4 h incubation, as determined by quantitative competitive RT -PCR. The concentrations of 15-HETE affecting gene expression were the same as those inducing protein degradation. Western blotting of cellular supernatants of myotubes treated with 15(S)-HETE for 24 h showed increased expression of p42, an ATPase subunit of the regulatory complex at similar concentrations, as well as a decrease in expression of myosin in the same concentration range. 15(S)-hydroxyeicosatetraenoic acid activated binding of nuclear factor-kB (NF-kB) in the myotube nucleus and stimulated degradation of I-kBa. The effect on the NF-kB/I-kBa system was attenuated by EPA. In addition, the NF-kB inhibitor peptide SN50 attenuated the increased chymotrypsinlike enzyme activity in the presence of 15(S)-HETE. These results suggest that 15(S)-HETE induces degradation of myofibrillar proteins in differentiated myotubes through an induction of an increased expression of the regulatory components of the ubiquitinproteasome proteolytic pathway possibly through the intervention of the nuclear transcription factor NF-kB, and that this process is inhibited by EPA.

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Section: Discussionmentioning

confidence: 99%

Induction of protein catabolism in myotubes by 15(S)-hydroxyeicosatetraenoic acid through increased expression of the ubiquitin–proteasome pathway

2003

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“…Lysosomal proteases, in particular cathepsins, are not the major mediators of myofibrillar protein degradation in rat skeletal muscle (Lowell et al, 1986;Tessitore et al, 1994). The ATP-ubiquitin-dependent proteolytic system is postulated to account for the turnover of short-lived proteins (Ciechanover et al, 1984) or for abnormal proteins formed during stress such as heat-shock (Bond et al, 1988).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-15 antagonizes muscle protein waste in tumour-bearing rats

et al. 2000

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Tissue protein hypercatabolism (TPH) is an important feature in cancer cachexia, particularly with regard to the skeletal muscle. The Yoshida AH-130 rat ascites hepatoma is a model system for studying the mechanisms involved in the processes that lead to tissue depletion, since it induces in the host a rapid and progressive muscle wasting, primarily due to TPH. The present study was aimed at investigating if IL-15, which is known to favour muscle fibre hypertrophy, could antagonize the enhanced muscle protein breakdown in this cancer cachexia model. Indeed, IL-15 treatment partly inhibited skeletal muscle wasting in AH-130-bearing rats by decreasing (8-fold) protein degradative rates (as measured by 14 C-bicarbonate pre-loading of muscle proteins) to values even lower than those observed in non-tumour-bearing animals. These alterations in protein breakdown rates were associated with an inhibition of the ATP-ubiquitin-dependent proteolytic pathway (35% and 41% for 2.4 and 1.2 kb ubiquitin mRNA, and 57% for the C8 proteasome subunit, respectively). The cytokine did not modify the plasma levels of corticosterone and insulin in the tumour hosts. The present data give new insights into the mechanisms by which IL-15 exerts its preventive effect on muscle protein wasting and seem to warrant the implementation of experimental protocols involving the use of the cytokine in the treatment of pathological states characterized by TPH, particularly in skeletal muscle, such as in the present model of cancer cachexia. © 2000 Cancer Research Campaign

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“…250 jim chloroquine and 10 mtm methylamine to block lysosomal acidification, together with 30 jim leupeptin. which inhibits lysosomal proteases (Lowell et al 1986: Tawa et al 1992: Baracos et al 1995.…”

Section: Materials and Methods Animalsmentioning

confidence: 99%

Mechanism of muscle protein degradation induced by a cancer cachectic factor

Lorite

Thompson²,

Drake³

et al. 1998

Br J Cancer

122

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Summary A proteolysis-inducing factor (PIF) isolated from a cachexia-inducing murne tumour (MAC16) produced a decrease in body weight (1.6 g, P. 0.01 compared with control subjects) within 24 h after i.v. administration to non-tumour-bearing mice. Weight loss was associated with significant decreases in the weight of the spleen and soleus and gastrocnemius muscles. with no effect on the weight of the heart or kidney and with an increase in weight of the liver. Protein degradation in isolated soleus muscle was signfficantly increased in mice bearing the MAC16 tumour. To define which proteolytic pathways contribute to this increase, soleus muscles from mice bearing the MAC16 tumour and non-tumour-bearing animals administered PIF were incubated under conditions that modify different proteolytic systems. In mice bearing the MAC16 tumour, there were increases in both cathepsin B and L, and the Ca2--dependent lysosomal and ATP-dependent pathways were found to contribute to the increased proteolysis; whereas, in PIF-injected animals, there was activation only of the ATP-dependent pathway. Further studies in mice bearing the MAC16 tumour have provided evidence for increased levels of ubiquitin-conjugated proteins and increased mRNA levels for the 14 kDa ubiquitin carrier protein E2 and the C9 proteasome subunit in gastrocnemius muscle, suggesting activation of the ATP-ubiquitin-dependent proteolytic pathway. A monoclonal antibody to PIF attenuated the enhanced protein degradation in soleus muscle from mice bearing the MAC16 tumour, confirming that PIF is responsible for the loss of skeletal muscle in cachectic mice.

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Evidence that lysosomes are not involved in the degradation of myofibrillar proteins in rat skeletal muscle

Cited by 213 publications

References 21 publications

Induction of protein catabolism in myotubes by 15(S)-hydroxyeicosatetraenoic acid through increased expression of the ubiquitin–proteasome pathway

Induction of protein catabolism in myotubes by 15(S)-hydroxyeicosatetraenoic acid through increased expression of the ubiquitin–proteasome pathway

Interleukin-15 antagonizes muscle protein waste in tumour-bearing rats

Mechanism of muscle protein degradation induced by a cancer cachectic factor

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