Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038187 (starvation)
 24,951 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Muscle damage with a lack of regeneration, manifests itself in several life-threatening diseases, including cancer cachexia, congestive heart failure, AIDS and sepsis. Often misdiagnosed as a condition simply of weight loss, cachexia is actually a highly complex metabolic disorder involving features of anorexia, anaemia, lipolysis and insulin resistance. A significant loss of lean body mass arises from such conditions, resulting in wasting of skeletal muscle. Unlike starvation, the weight loss seen in chronic illnesses arises equally from loss of muscle and of fat. The cachectic state is particularly problematic in cancer, typifying poor prognosis and often lowering responses to chemotherapy and radiation treatment. More than half of cancer patients suffer from cachexia, and strikingly, nearly one-third of cancer deaths are related to cachexia rather than the tumour burden. In considering this disorder, we are faced with a conundrum; how is it possible for uncontrolled growth to prevail in the tumour, in the face of unrestrained tissue loss in our muscles? Consistently, the catabolic state has been associated with a shift in the homeostatic balance between muscle synthesis and degradation mediated by the actions of growth factors and cytokines. Indeed, tumour necrosis factor-alpha (TNF-alpha) levels are raised in several animal models of cachectic muscle wasting, whereas the insulin-like growth factor (IGF) system acts potently to regulate muscle development, hypertrophy and maintenance. This concept of skeletal muscle homeostasis, often viewed as the net balance between two separate processes of protein synthesis and degradation has however changed. More recently, the view is that these two biochemical processes are not occurring independently of each other but in fact are finely co-ordinated by a web of intricate signalling networks. This review, therefore, aims to discuss data currently available regarding the mechanisms of degeneration and regeneration with specific emphasis on the potential and controversial cross-talk which may exist between anabolic growth factors (e.g. IGF-I) and catabolic cytokines (e.g. TNF-alpha). Also importantly, the potential impact at a cellular level of exercise, diet and age will be addressed. Finally, the ability to 'hi-jack' signalling pathways traditionally believed to be for growth and survival or death will be reviewed. It is anticipated that such a review will highlight significant gaps in our knowledge of the cachectic state as well as provide caution with regards to therapeutics suggesting total block on inflammatory processes such as that associated with TNF-alpha action.
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PMID:Waste management - cytokines, growth factors and cachexia. 1711 96

Severe or chronic disease can lead to cachexia which involves weight loss and muscle wasting. Cancer cachexia contributes significantly to disease morbidity and mortality. Multiple studies have shown that the metabolic changes that occur with cancer cachexia are unique compared to that of starvation. Specifically, cancer patients seem to lose a larger proportion of skeletal muscle mass. There are three pathways that contribute to muscle protein degradation: the lysosomal system, cytosolic proteases and the ubiquitin (Ub)-proteasome pathway. The Ub-proteasome pathway seems to account for the majority of skeletal muscle degradation in cancer cachexia and is stimulated by several cytokines including tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, interferon-gamma and proteolysis-inducing factor. Cachexia is particularly severe in pancreatic cancer and contributes significantly to the quality of life and mortality of these patients. Several factors contribute to weight loss in these patients, including alimentary obstruction, pain, depression, side effects of therapy and a high catabolic state. Although no single agent has proven to halt cachexia in these patients there has been some progress in the areas of nutrition with supplementation and pharmacological agents such as megesterol acetate, steroids and experimental trials targeting cytokines that stimulate the Ub-proteasome pathway.
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PMID:Mechanisms of skeletal muscle degradation and its therapy in cancer cachexia. 1745 54

Autophagy allows cell survival during starvation through the bulk degradation of proteins and organelles by lysosomal enzymes. However, the mechanisms responsible for the induction and regulation of the autophagy program are poorly understood. Here we show that the FoxO3 transcription factor, which plays a critical role in muscle atrophy, is necessary and sufficient for the induction of autophagy in skeletal muscle in vivo. Akt/PKB activation blocks FoxO3 activation and autophagy, and this effect is not prevented by rapamycin. FoxO3 controls the transcription of autophagy-related genes, including LC3 and Bnip3, and Bnip3 appears to mediate the effect of FoxO3 on autophagy. This effect is not prevented by proteasome inhibitors. Thus, FoxO3 controls the two major systems of protein breakdown in skeletal muscle, the ubiquitin-proteasomal and autophagic/lysosomal pathways, independently. These findings point to FoxO3 and Bnip3 as potential therapeutic targets in muscle wasting disorders and other degenerative and neoplastic diseases in which autophagy is involved.
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PMID:FoxO3 controls autophagy in skeletal muscle in vivo. 1805 11

During pathophysiological muscle wasting, a family of ubiquitin ligases, including muscle RING-finger protein-1 (MuRF1), has been proposed to trigger muscle protein degradation via ubiquitination. Here, we characterized skeletal muscles from wild-type (WT) and MuRF1 knockout (KO) mice under amino acid (AA) deprivation as a model for physiological protein degradation, where skeletal muscles altruistically waste themselves to provide AAs to other organs. When WT and MuRF1 KO mice were fed a diet lacking AA, MuRF1 KO mice were less susceptible to muscle wasting, for both myocardium and skeletal muscles. Under AA depletion, WT mice had reduced muscle protein synthesis, while MuRF1 KO mice maintained nonphysiologically elevated levels of skeletal muscle protein de novo synthesis. Consistent with a role of MuRF1 for muscle protein turnover during starvation, the concentrations of essential AAs, especially branched-chain AAs, in the blood plasma significantly decreased in MuRF1 KO mice under AA deprivation. To clarify the molecular roles of MuRF1 for muscle metabolism during wasting, we searched for MuRF1-associated proteins using pull-down assays and mass spectrometry. Muscle-type creatine kinase (M-CK), an essential enzyme for energy metabolism, was identified among the interacting proteins. Coexpression studies revealed that M-CK interacts with the central regions of MuRF1 including its B-box domain and that MuRF1 ubiquitinates M-CK, which triggers the degradation of M-CK via proteasomes. Consistent with MuRF1's role of adjusting CK activities in skeletal muscles by regulating its turnover in vivo, we found that CK levels were significantly higher in the MuRF1 KO mice than in WT mice. Glucocorticoid modulatory element binding protein-1 and 3-hydroxyisobutyrate dehydrogenase, previously identified as potential MuRF1-interacting proteins, were also ubiquitinated MuRF1-dependently. Taken together, these data suggest that, in a multifaceted manner, MuRF1 participates in the regulation of AA metabolism, including the control of free AAs and their supply to other organs under catabolic conditions, and in the regulation of ATP synthesis under metabolic-stress conditions where MuRF1 expression is induced.
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PMID:Muscle RING-finger protein-1 (MuRF1) as a connector of muscle energy metabolism and protein synthesis. 1822 70

Under various pathophysiological muscle-wasting conditions, such as diabetes and starvation, a family of ubiquitin ligases, including muscle-specific RING-finger protein 1 (MuRF1), are induced to target muscle proteins for degradation via ubiquitination. We have generated transgenic mouse lines over-expressing MuRF1 in a skeletal muscle-specific fashion (MuRF1-TG mice) in an attempt to identify the in vivo targets of MuRF1. MuRF1-TG lines were viable, had normal fertility and normal muscle weights at eight weeks of age. Comparison of quadriceps from MuRF1-TG and wild type mice did not reveal elevated multi-ubiquitination of myosin as observed in human patients with muscle wasting. Instead, MuRF1-TG mice expressed lower levels of pyruvate dehydrogenase (PDH), a mitochondrial key enzyme in charge of glycolysis, and of its regulator PDK2. Furthermore, yeast two-hybrid interaction studies demonstrated the interaction of MuRF1 with PDH, PDK2, PDK4, PKM2 (all participating in glycolysis) and with phosphorylase beta (PYGM) and glycogenin (both regulating glycogen metabolism). Consistent with the idea that MuRF1 may regulate carbohydrate metabolism, MuRF1-TG mice had twofold elevated insulin blood levels and lower hepatic glycogen contents. To further examine MuRF1's role for systemic carbohydrate regulation, we performed glucose tolerance tests (GTT) in wild type and MuRF1-TG mice. During GTT, MuRF1-TG mice developed striking hyperinsulinaemia and hepatic glycogen stores, that were depleted at basal levels, became rapidly replenished. Taken together, our data demonstrate that MuRF1 expression in skeletal muscle re-directs glycogen synthesis to the liver and stimulates pancreatic insulin secretion, thereby providing a regulatory feedback loop that connects skeletal muscle metabolism with the liver and the pancreas during metabolic stress.
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PMID:MuRF1-dependent regulation of systemic carbohydrate metabolism as revealed from transgenic mouse studies. 1846 20

Approximately two thirds of cancer patients at advanced stages of the disease suffer from anorexia, which leads to significant weight loss and progressive cachexia, an important factor that contributes to death. It has been observed that cancer cachexia differs from simple starvation, although the exact mechanisms associated with cancer cachexia are not well known. Several theories regarding its pathogenesis point to a complex mixture of tumor, host and treatment variables. Unfortunately, the wasting syndrome also constitutes for the patient, a progression of the cancer process, significantly affecting quality of life and social interactions. Treatable causes should be identified and treated. Knowledge of the mechanisms underlying the effects of caquexia on the patient may play a role in identifying treatment measures targetted to muscle wasting and to maintain body strength. In this article we review the main features and mechanisms of the anorexia-cachexia syndrome in patients with cancer.
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PMID:[The cachexia-anorexia syndrome among oncological patients]. 1904 64

Beta-hydroxy-beta-methylbutyrate (HMB), a leucine catabolite, has been shown to prevent exercise-induced protein degradation and muscle damage. We hypothesized that HMB would directly regulate muscle-cell proliferation and differentiation and would attenuate apoptosis, the latter presumably underlying satellite-cell depletion during muscle degradation or atrophy. Adding various concentrations of HMB to serum-starved myoblasts induced cell proliferation and MyoD expression as well as the phosphorylation of MAPK/ERK. HMB induced differentiation-specific markers, increased IGF-I mRNA levels and accelerated cell fusion. Its inhibition of serum-starvation- or staurosporine-induced apoptosis was reflected by less apoptotic cells, reduced BAX expression and increased levels of Bcl-2 and Bcl-X. Annexin V staining and flow cytometry analysis showed reduced staurosporine-induced apoptosis in human myoblasts in response to HMB. HMB enhanced the association of the p85 subunit of PI3K with tyrosine-phosphorylated proteins. HMB elevated Akt phosphorylation on Thr308 and Ser473 and this was inhibited by Wortmannin, suggesting that HMB acts via Class I PI3K. Blocking of the PI3K/Akt pathway with specific inhibitors revealed its requirement in mediating the promotive effects of HMB on muscle cell differentiation and fusion. These direct effects of HMB on myoblast differentiation and survival resembling those of IGF-I, at least in culture, suggest its positive influence in preventing muscle wasting.
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PMID:Beta-hydroxy-beta-methylbutyrate (HMB) stimulates myogenic cell proliferation, differentiation and survival via the MAPK/ERK and PI3K/Akt pathways. 1921 Oct 28

Glutamine depletion in skeletal muscle of severely ill patients is an outstanding metabolic marker related to acute skeletal muscle wasting. To date it is unclear why intracellular glutamine concentrations are lowered in skeletal muscle to such an extent when simultaneously muscular glutamine synthesis and release are stimulated. This essay introduces a hypothesis that intracellular glutamine deficiency is part of a metabolic program maintaining cell integrity. This program seems to resemble short-term hibernation, which can be observed in various mammalian species during periods of starvation. Interestingly, even in septic patients who do not survive, there are no signs of apoptosis or necrosis in affected organs. Therefore, in severe illness evolutionarily conserved energy saving programs may be switched on for protecting the organs in a mode reminiscent of hibernation. This would explain the low energy expenditure as described for septic patients and the limited success of nutrition in avoiding skeletal muscle atrophy in sepsis.
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PMID:Hypothesis: Muscular glutamine deficiency in sepsis--a necessary step for a hibernation-like state? 2007 Nov 42

Malnutrition is an umbrella term that includes starvation, sarcopenia, and cachexia; however, differentiating between these terms is infrequent in clinical practice. Given that the effectiveness of treatment depends on the aetiology of unintentional weight loss, it is important that clinicians are aware of the defining characteristics. The aim of this study was to determine whether Australian dietitians understand and use the terms starvation, sarcopenia, and cachexia and provide targeted treatment strategies accordingly. Members of the Dietitians Association of Australia were surveyed to gain information on practices and attitudes to diagnosis and treatment of adult malnutrition. In addition, three case studies were provided to examine understanding of starvation, sarcopenia, and cachexia. 221 dietitians accessed the survey. 81 respondents (43%) indicated the use of at least one alternate term (starvation, sarcopenia, and/or cachexia). Muscle wasting was the most commonly used diagnostic criterion. High-energy high-protein diet was the most common therapy prescribed. Correct diagnoses for case studies were recorded by 6% of respondents for starvation, 46% for sarcopenia, and 21% for cachexia. There is a need for increased awareness of the existence of starvation, sarcopenia, and cachexia amongst Australian dietitians and research into appropriate methods of identification and treatment for each condition.
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PMID:The challenge of appropriate identification and treatment of starvation, sarcopenia, and cachexia: a survey of Australian dietitians. 2223 70

Skeletal muscle, the main protein reservoir in the body, is a tissue that exhibits high plasticity when exposed to changes. Muscle proteins can be mobilized into free amino acids when skeletal muscle wasting occurs, a process called skeletal muscle atrophy. This wasting is an important systemic or local manifestation under disuse conditions (e.g., bed rest or immobilization), in starvation, in older adults, and in several diseases. The molecular mechanisms involved in muscle wasting imply the activation of specific signaling pathways which ultimately manage muscle responses to modulate biological events such as increases in protein catabolism, oxidative stress, and cell death by apoptosis. Many factors have been involved in the generation and maintenance of atrophy in skeletal muscle, among them angiotensin II (Ang-II), the main peptide of renin-angiotensin system (RAS). Together with Ang-II, the angiotensin-converting enzyme (ACE) and the Ang-II receptor type 1 (AT-1 receptor) are expressed in skeletal muscle, forming an important local axis that can regulate its function. In many of the conditions that lead to muscle wasting, there is an impairment of RAS in a global or local fashion. At this point, there are several pieces of evidence that suggest the participation of Ang-II, ACE, and AT-1 receptor in the generation of skeletal muscle atrophy. Interestingly, the Ang-II participation in muscle atrophy is strongly ligated to the regulation of hypertrophic activity of factors such as insulin-like growth factor 1 (IGF-1). In this article, we reviewed the current state of Ang-II and RAS function on skeletal muscle wasting and its possible use as a therapeutic target to improve skeletal muscle function under atrophic conditions.
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PMID:Angiotensin II: role in skeletal muscle atrophy. 2297 90


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