Muscle Cachexia: Current Concepts of Intracellular Mechanisms and Molecular Regulation

Hasselgren, Per-Olof; Fischer, Josef E.

doi:10.1097/00000658-200101000-00003

Cited by 240 publications

(161 citation statements)

References 67 publications

Supporting

Mentioning

156

Contrasting

Unclassified

Order By: Relevance

“…Interestingly, the double treatment also decreased m‐calpain gene expression, known to play a role in muscle proteolysis in cancer cachexia 43, 44. Indeed, it was suggested that calcium‐dependent proteases participate in the release of myofilaments from the sarcomere, and these myofilaments would be later degraded by the ubiquitin‐dependent proteolytic system 45. Sandri et al reported the role for lysosome activity in muscle degradation during cancer cachexia.…”

Section: Resultsmentioning

confidence: 99%

A multifactorial anti-cachectic approach for cancer cachexia in a rat model undergoing chemotherapy

Toledo

Penna

Oliva

et al. 2015

Journal of Cachexia, Sarcopenia and Muscle

View full text Add to dashboard Cite

BackgroundThe effectiveness of drugs aimed at counteracting cancer cachexia is generally tested in pre‐clinical rodent models, where only the tumour‐induced alterations are taken into account, excluding the co‐presence of anti‐tumour molecules that could worsen the scenario and/or interfere with the treatment.MethodsThe aim of the present investigation has been to assess the efficacy of a multifactorial treatment, including formoterol and megestrol acetate, in cachectic tumour‐bearing rats (Yoshida AH‐130, a highly cachectic tumour) undergoing chemotherapy (sorafenib).ResultsTreatment of cachectic tumour‐bearing rats with sorafenib (90 mg/kg) causes an important decrease in tumour cell content due to both reduced cell proliferation and increased apoptosis. As a consequence, animal survival significantly improves, while cachexia occurrence persists. Multi‐factorial treatment using both formoterol and megestrol acetate is highly effective in preventing muscle wasting and has more powerful effects than the single formoterol administration. In addition, both physical activity and grip strength are significantly improved as compared with the untreated tumour‐bearing animals. The effects of the multi‐factorial treatment include increased food intake (likely due to megestrol acetate) and decreased protein degradation, as shown by the reduced expression of genes associated with both proteasome and calpain proteolytic systems.ConclusionsThe combination of the two drugs proved to be a promising strategy for treating cancer cachexia in a pre‐clinical setting that better resembles the human condition, thus providing a strong rationale for the use of such combination in clinical trials involving cachectic cancer patients.

show abstract

Section: Resultsmentioning

confidence: 99%

A multifactorial anti-cachectic approach for cancer cachexia in a rat model undergoing chemotherapy

Toledo

Penna

Oliva

et al. 2015

Journal of Cachexia, Sarcopenia and Muscle

View full text Add to dashboard Cite

show abstract

“…These two processes have been suggested to contribute less than 15 -20% towards total protein breakdown in muscle (Attaix et al, 1998;Lecker et al, 1999) and do not breakdown myofibrillar proteins (Lovell et al, 1986). However, the calcium/calpain pathway has been suggested to release myofilaments from the sarcomere in an early and perhaps rate-limiting component of the catabolic response in muscle (Hasselgren and Fischer, 2001). Further catabolism of the actin and myosin released from the myofilaments is considered to occur via the ubiquitin-proteasome proteolytic pathway.…”

Section: Discussionmentioning

confidence: 99%

Expression of the ubiquitin-proteasome pathway and muscle loss in experimental cancer cachexia

et al. 2005

View full text Add to dashboard Cite

Muscle protein degradation is thought to play a major role in muscle atrophy in cancer cachexia. To investigate the importance of the ubiquitin-proteasome pathway, which has been suggested to be the main degradative pathway mediating progressive protein loss in cachexia, the expression of mRNA for proteasome subunits C2 and C5 as well as the ubiquitin-conjugating enzyme, E2 14k , has been determined in gastrocnemius and pectoral muscles of mice bearing the MAC16 adenocarcinoma, using competitive quantitative reverse transcriptase polymerase chain reaction. Protein levels of proteasome subunits and E2 14k were determined by immunoblotting, to ensure changes in mRNA were reflected in changes in protein expression. Muscle weights correlated linearly with weight loss during the course of the study. There was a good correlation between expression of C2 and E2 14k mRNA and protein levels in gastrocnemius muscle with increases of 6 -8-fold for C2 and two-fold for E2 14k between 12 and 20% weight loss, followed by a decrease in expression at weight losses of 25 -27%, although loss of muscle protein continued. In contrast, expression of C5 mRNA only increased two-fold and was elevated similarly at all weight losses between 7.5 and 27%. Both proteasome functional activity, and proteasome-specific tyrosine release as a measure of total protein degradation was also maximal at 18 -20% weight loss and decreased at higher weight loss. Proteasome expression in pectoral muscle followed a different pattern with increases in C2 and C5 and E2 14k mRNA only being seen at weight losses above 17%, although muscle loss increased progressively with increasing weight loss. These results suggest that activation of the ubiquitin-proteasome pathway plays a major role in protein loss in gastrocnemius muscle, up to 20% weight loss, but that other factors such as depression in protein synthesis may play a more important role at higher weight loss.

show abstract

“…Protein hypercatabolism and muscle wasting characterize catabolic states induced by sepsis and trauma (Hasselgren & Fischer 2001). The mechanisms responsible for these changes have not been completely elucidated.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of TNF-alpha production by pentoxifylline does not prevent endotoxin-induced decrease in serum IGF-I

Colson

Willems²,

Thissen

2003

Journal of Endocrinology

View full text Add to dashboard Cite

Sepsis and endotoxin (LPS or lipopolysaccharide) injection induce a state of growth hormone (GH) resistance leading to decreased circulating insulin-like growth factor (IGF)-I. Because the proinflammatory cytokines tumor necrosis factor (TNF)-and interleukin (IL)-1 inhibit the GHstimulated IGF-I expression in vitro, it was tempting to speculate that these two cytokines might play an important role in the reduction of circulating IGF-I levels caused by LPS. Pentoxifylline, a methylxanthine usually used in the treatment of peripheral arterial circulatory disorders, has been reported to inhibit TNF-synthesis. The goal of our study was to investigate whether inhibition of TNFproduction by pentoxifylline could prevent the decrease in IGF-I and the GH resistance caused by LPS injection. Because previous studies demonstrated that pentoxifylline can reduce muscle catabolism induced by sepsis, we also assessed whether pentoxifylline could exert its anticatabolic effect by preventing the decrease in circulating IGF-I. LPS injection in rats decreased serum IGF-I ( 45% at 12 h; P,0·01 vs time 0) and its liver mRNA ( 67% at 12 h; P,0·01 vs time 0) while it induced circulating TNF-and IL-1 and their hepatic expression (P,0·01). Pretreatment of LPS-treated animals by pentoxifylline abolished the LPS-induced rise in serum TNF-( 98% at 90 min; P,0·001 vs LPS alone) and to a lesser extent in serum IL-1 ( 44% at 3 h; not significant vs LPS alone). Despite its dramatic inhibitory effect on TNF-induction, however, pentoxifylline failed to suppress both the decrease in IGF-I and the GH resistance induced by LPS in rats. These results suggest that mediators other than TNF-, in particular IL-1 or IL-6, could contribute to the GH resistance induced by LPS. They also suggest that the anticatabolic effect of pentoxifylline is not due to prevention of the decline of circulating IGF-I.

show abstract

Muscle Cachexia: Current Concepts of Intracellular Mechanisms and Molecular Regulation

Cited by 240 publications

References 67 publications

A multifactorial anti-cachectic approach for cancer cachexia in a rat model undergoing chemotherapy

A multifactorial anti-cachectic approach for cancer cachexia in a rat model undergoing chemotherapy

Expression of the ubiquitin-proteasome pathway and muscle loss in experimental cancer cachexia

Inhibition of TNF-alpha production by pentoxifylline does not prevent endotoxin-induced decrease in serum IGF-I

Contact Info

Product

Resources

About