leptin and Muscular-Atrophy

In patients with chronic obstructive pulmonary disease (COPD), malnutrition and limited physical activity are very common and contribute to disease prognosis, whereas a balance between caloric intake and exercise allows body weight stability and muscle mass preservation. The goal of this review is to analyze the implications of chronic hypoxia on three key elements involved in energy homeostasis and its role in COPD cachexia. The first one is energy intake. Body weight loss, often observed in patients with COPD, is related to lack of appetite. Inflammatory cytokines are known to be involved in anorexia and to be correlated to arterial partial pressure of oxygen. Recent studies in animals have investigated the role of hypoxia in peptides involved in food consumption such as leptin, ghrelin, and adenosine monophosphate activated protein kinase. The second element is muscle function, which is strongly related to energy use. In COPD, muscle atrophy and muscle fiber shift to the glycolytic type might be an adaptation to chronic hypoxia to preserve the muscle from oxidative stress. Muscle atrophy could be the result of a marked activation of the ubiquitin-proteasome pathway as found in muscle of patients with COPD. Hypoxia, via hypoxia inducible factor-1, is implicated in mitochondrial biogenesis and autophagy. Third, hormonal control of energy balance seems to be affected in patients with COPD. Insulin resistance has been described in this group of patients as well as a sort of "growth hormone resistance." Hypoxia, by hypoxia inducible factor-1, accelerates the degradation of tri-iodothyronine and thyroxine, decreasing cellular oxygen consumption, suggesting an adaptive mechanism rather than a primary cause of COPD cachexia. COPD rehabilitation aimed at maintaining function and quality of life needs to address body weight stabilization and, in particular, muscle mass preservation.

Topics: Anorexia; Appetite; Cachexia; Cytokines; Energy Intake; Energy Metabolism; Exercise; Ghrelin; Human Growth Hormone; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Leptin; Malnutrition; Muscular Atrophy; Nutritional Status; Oxygen; Pulmonary Disease, Chronic Obstructive

Chronic inflammation is associated with cachexia and increased mortality risk in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Inflammation suppresses appetite and causes the loss of protein stores. In CKD patients, increased serum levels of pro-inflammatory cytokines may be caused by reduced renal function, volume overload, oxidative or carbonyl stress, decreased levels of antioxidants, increased susceptibility to infection in uremia, and the presence of comorbid conditions. Cachexia is brought about by the synergistic combination of a dramatic decrease in appetite and an increase in the catabolism of fat and lean body mass. Pro-inflammatory cytokines act on the central nervous system to alter appetite and energy metabolism and to provide a signal-through the nuclear factor-kappaB and ATP-ubiquitin-dependent proteolytic pathways-that causes muscle wasting. Further research into the molecular pathways leading to inflammation and cachexia may lead to novel therapeutic therapies for this devastating and potentially fatal complication of chronic disease.

Topics: Cachexia; Cardiovascular Diseases; Chronic Disease; Cytokines; Feeding and Eating Disorders; Humans; Inflammation; Kidney Failure, Chronic; Leptin; Muscular Atrophy; Neuropeptides

Liver cirrhosis in the advanced state is characterized by protein wasting, as indicated by the loss of muscle mass, hypoalbuminemia, and an abnormal amino acid profile. The protein wasting condition cirrhosis is associated with a poor prognosis and reduced survival. Poor nutrition, metabolic and hormonal abnormalities, and other disease-associated alterations may all concur to protein wasting. An understanding of the causes and mechanisms leading to protein wasting in cirrhosis may help in the development of nutritional interventions and new therapies.. Albumin and muscle protein turnover in cirrhotic patients have been studied in vivo with the aid of isotope dilution techniques or organ catheterization. Albumin synthesis appears to parallel liver function, i.e. the more compromised is the liver, the less is the albumin production rate. Meal-induced albumin synthesis is impaired even in compensated cirrhotic patients. Skeletal muscle protein synthesis is diminished in cirrhosis, and total muscle protein breakdown also appears to be increased, thus explaining the reduced muscle mass. Either hormone or substrate resistance, or newly involved substances (cytokines, insulin-like growth factor 1, leptin) may play a role in the reduced synthesis of both albumin and muscle proteins in liver cirrhosis.. Abnormalities of both albumin and muscle protein turnover have been demonstrated in liver cirrhotic patients. The possible role of the multiple hormonal and metabolic abnormalities of this disease, as well that of cytokines and other recently discovered substances, need to be investigated further.

Topics: Albumins; Cytokines; Humans; Insulin-Like Growth Factor I; Leptin; Liver Cirrhosis; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; Myofibrils

Over the lifespan there is a decline in food intake. This has been termed the physiological anorexia of aging. It has many causes, including alterations in the gastrointestinal satiating system, the effect of elevated leptin levels, especially in men, and a variety of changes in central nervous system neurotransmitters. Beyond the age of 70 years body mass declines. This includes both loss of adipose tissue and muscle mass. The loss of muscle mass in older individuals is termed sarcopenia. There is increasing evidence that this is caused, in men, partly by the decline in testosterone. Illness results in an increase of cytokines that produce both anorexia and cause protein wasting. Many of the causes of cachexia in older individuals are treatable. Depression is the most common cause of weight loss in older individuals. Dieting in older individuals is associated with a loss of skeletal tissue as well as fat mass. This can place older individuals at risk of becoming the 'fat frail'.

Topics: Aged; Aging; Anorexia; Body Composition; Cytokines; Diet, Reducing; Female; Food Services; Humans; Leptin; Male; Muscular Atrophy; Testosterone; Weight Loss

Leptin is a hormone that plays a key role in controlling food intake and energy homeostasis. Skeletal muscle is an important target for leptin and recent studies have shown that leptin deficiency may lead to muscular atrophy. However, leptin deficiency-induced structural changes in muscles are poorly understood. The zebrafish has emerged as an excellent model organism for studies of vertebrate diseases and hormone response mechanisms. In this study, we explored ex-vivo magnetic resonance microimaging (μMRI) methods to non-invasively assess muscle wasting in leptin-deficient (lepb-/-) zebrafish model. The fat mapping performed by using chemical shift selective imaging shows significant fat infiltration in muscles of lepb-/- zebrafish compared to control zebrafish. T2 relaxation measurements show considerably longer T2 values in the muscle of lepb-/- zebrafish. Multiexponential T2 analysis detected a significantly higher value and magnitude of long T2 component in the muscles of lepb-/- as compared to control zebrafish. For further zooming into the microstructural changes, we applied diffusion-weighted MRI. The results show a significant decrease in the apparent diffusion coefficient indicating increased constraints of molecular movements within the muscle regions of lepb-/- zebrafish. The use of the phasor transformation for the separation of diffusion-weighted decay signals showed a bi-component diffusion system which allows us to estimate each fraction on a voxel-wise basis. A substantial difference was found between the ratio of two components in lepb-/- and control zebrafish muscles, indicating alterations in diffusion behavior associated with the tissue microstructural changes in muscles of lepb-/- zebrafish as compared to control zebrafish. Taken together, our results demonstrate that the muscles of lepb-/- zebrafish undergo significant fat infiltration and microstructural changes leading to muscle wasting. This study also demonstrates that μMRI provides excellent means to non-invasively study the microstructural changes in the muscles of the zebrafish model.

Topics: Animals; Diffusion Magnetic Resonance Imaging; Leptin; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Muscle, Skeletal; Muscular Atrophy; Zebrafish

The role and significance of liver-derived cytokines in cancer-associated cachexia syndrome remain elusive. Here we report that combinatorial counterbalances of the leptin and Igf1 signaling pathways in hepatocellular carcinoma (HCC) models significantly relieves cachexia. Double transgenic zebrafish models of HCC that stably displayed focal lesions, anorexia, and wasting of adipose and muscle tissues were first generated. Knockout of lepr or mc4r from these zebrafish partially restored appetite and exerted moderate or no effect on tissue wasting. However, genetic replenishment of Igf1 in a lepr-mutant background effectively relieved the cachexia-like phenotype without affecting tumor growth. Similarly, administration of napabucasin, a Stat3/Socs3 inhibitor, on the zebrafish HCC model, mammalian cell lines with exogenous IGF1, and two mouse xenograft models restored insulin sensitivity and rescued the wasting of nontumor tissues. Together, these results describe the synergistic impact of leptin and Igf1 normalization in treating certain HCC-associated cachexia as a practical strategy. SIGNIFICANCE: Disruption of leptin signaling with normalized Igf1 expression significantly rescues anorexia, muscle wasting, and adipose wasting in Ras- and Myc-driven zebrafish models of HCC.

Topics: 3T3-L1 Cells; Adipose Tissue; Animals; Animals, Genetically Modified; Benzofurans; Cachexia; Carcinoma, Hepatocellular; Cells, Cultured; Cytokines; Disease Models, Animal; Drug Synergism; HEK293 Cells; Hep G2 Cells; Humans; Insulin Resistance; Insulin-Like Growth Factor I; Leptin; Liver; Liver Neoplasms; Mice; Muscular Atrophy; Naphthoquinones; Receptors, Leptin; Signal Transduction; Wasting Syndrome; Xenograft Model Antitumor Assays; Zebrafish

Cancer cachexia affects up to 80% of patients with advanced solid cancer and leads to excessive muscle wasting. Here, using an inducible zebrafish hepatocellular carcinoma (HCC) model driven by oncogenic

Topics: Animals; Carcinogenesis; Carcinoma, Hepatocellular; Disease Models, Animal; Fatty Liver; Feeding Behavior; Gene Knockout Techniques; Humans; Leptin; Liver Neoplasms; Male; Muscular Atrophy; Mutation; Proto-Oncogene Proteins p21(ras); Receptors, Leptin; Signal Transduction; Up-Regulation; Zebrafish; Zebrafish Proteins

Glucocorticoids (GCs) are potent pharmacological agents used to treat a number of immune conditions. GCs are also naturally occurring steroid hormones (e.g. cortisol, corticosterone) produced in response to stressful conditions that are thought to increase the preference for calorie dense 'comfort' foods. If chronically elevated, GCs can contribute to the development of type 2 diabetes mellitus (T2DM), although the mechanisms for the diabetogenic effects are not entirely clear. The present study proposes a new rodent model to investigate the combined metabolic effects of elevated GCs and high-fat feeding on ectopic fat deposition and diabetes development. Male Sprague-Dawley rats (aged 7-8 weeks) received exogenous corticosterone or wax (placebo) pellets, implanted subcutaneously, and were fed either a standard chow diet (SD) or a 60% high-fat diet (HFD) for 16 days. Animals given corticosterone and a HFD (cort-HFD) had lower body weight and smaller relative glycolytic muscle mass, but increased relative epididymal mass, compared with controls (placebo-SD). Cort-HFD rats exhibited severe hepatic steatosis and increased muscle lipid deposition compared with placebo-SD animals. Moreover, cort-HFD animals were found to exhibit severe fasting hyperglycemia (60% increase), hyperinsulinemia (80% increase), insulin resistance (60% increase) and impaired β-cell response to oral glucose load (20% decrease) compared with placebo-SD animals. Thus, a metabolic syndrome or T2DM phenotype can be rapidly induced in young Sprague-Dawley rats by using exogenous GCs if a HFD is consumed. This finding might be valuable in examining the physiological and molecular mechanisms of GC-induced metabolic disease.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; Adipose Tissue; Adiposity; Animals; Body Composition; Circadian Rhythm; Corticosterone; Diabetes Mellitus, Experimental; Diet, High-Fat; Disease Models, Animal; Energy Intake; Fasting; Feeding Behavior; Glucocorticoids; Hyperglycemia; Hyperinsulinism; Hyperphagia; Insulin; Insulin Resistance; Leptin; Male; Muscular Atrophy; Rats; Receptors, Glucocorticoid; Triglycerides; Weight Gain

Supra-physiological levels of vitamin D induce skeletal muscle atrophy, which may be particularly detrimental in already sarcopaenic elderly. Neither the cause nor whether the atrophy is fibre type specific are known. To obtain supraphysiological levels of circulating vitamin D (1,25(OH)(2)D(3)) 27.5-month-old female Fischer(344) × Brown Norway F1 rats were orally treated for 6 weeks with vehicle or the vitamin D analogue alfacalcidol. Alfacalcidol treatment induced a 22% decrease in body mass and 17% muscle atrophy. Fibre atrophy was restricted to type IIb fibres in the low-oxidative part of the gastrocnemius medialis only (-22%; P < 0.05). There was a concomitant 1.6-fold increase in mRNA expression of the ubiquitin ligase MuRF-1 (P < 0.001), whereas those of insulin-like growth factor 1 and myostatin were not affected. Circulating IL-6 was unaltered, but leptin and adiponectin were decreased (-39%) and increased (64%), respectively. The treated rats also exhibited a reduced food intake. In conclusion, supraphysiological levels of circulating 1,25(OH)(2)D(3) cause preferential atrophy of type IIb fibres, which is associated with an increased expression of MuRF-1 without evidence of systemic inflammation. The atrophy and loss of body mass in the presence of supra-physiological levels of vitamin D are primarily due to a reduced food intake.

Topics: Adiponectin; Animals; Body Mass Index; Dietary Supplements; Eating; Female; Hydroxycholecalciferols; Inflammation; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Interleukin-6; Leptin; Muscle Fibers, Skeletal; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; Myostatin; Organ Size; Rats; RNA, Messenger; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Vitamin D

Age-associated loss of muscle mass, or sarcopenia, contributes directly to frailty and an increased risk of falls and fractures among the elderly. Aged mice and elderly adults both show decreased muscle mass as well as relatively low levels of the fat-derived hormone leptin. Here we demonstrate that loss of muscle mass and myofiber size with aging in mice is associated with significant changes in the expression of specific miRNAs. Aging altered the expression of 57 miRNAs in mouse skeletal muscle, and many of these miRNAs are now reported to be associated specifically with age-related muscle atrophy. These include miR-221, previously identified in studies of myogenesis and muscle development as playing a role in the proliferation and terminal differentiation of myogenic precursors. We also treated aged mice with recombinant leptin, to determine whether leptin therapy could improve muscle mass and alter the miRNA expression profile of aging skeletal muscle. Leptin treatment significantly increased hindlimb muscle mass and extensor digitorum longus fiber size in aged mice. Furthermore, the expression of 37 miRNAs was altered in muscles of leptin-treated mice. In particular, leptin treatment increased the expression of miR-31 and miR-223, miRNAs known to be elevated during muscle regeneration and repair. These findings suggest that aging in skeletal muscle is associated with marked changes in the expression of specific miRNAs, and that nutrient-related hormones such as leptin may be able to reverse muscle atrophy and alter the expression of atrophy-related miRNAs in aging skeletal muscle.

Topics: Aging; Animals; Gene Expression Profiling; Leptin; Mice; Mice, Inbred C57BL; MicroRNAs; Muscle Development; Muscle, Skeletal; Muscular Atrophy

Excess lipid accumulation resulting from an elevated supply of plasma fatty acids is linked to the pathogenesis of the metabolic syndrome and heart disease. The term 'lipotoxicity' was coined to describe how lipid accumulation leads to cellular dysfunction and death in non-adipose tissues including the heart, pancreas and liver. While lipotoxicity has been shown in cultured skeletal muscle cells, the degree of lipotoxicity in vivo and the functional consequences are unresolved. We studied three models of fatty acid overload in male mice: 5 h Intralipid((R)) and heparin infusion, prolonged high fat feeding (HFF) and genetic obesity induced by leptin deficiency (ob/ob mice). Markers of apoptosis, proteolysis and autophagy were assessed as readouts of lipotoxicity. The Intralipid((R)) infusion increased caspase 3 activity in skeletal muscle, demonstrating that enhancing fatty acid flux activates pro-apoptotic pathways. HFF and genetic obesity increased tissue lipid content but did not influence apoptosis. Gene array analysis revealed that HFF reduced the expression of 31 pro-apoptotic genes. Markers of autophagy (LC3beta and beclin-1 expression) were unaffected by HFF and were associated with enhanced Bcl(2) protein expression. Proteolytic activity was similarly unaffected by HFF or in ob/ob mice. Thus, contrary to our previous findings in muscle culture in vitro and in other non-adipose tissues in vivo, lipid overload did not induce apoptosis, autophagy or proteolysis in skeletal muscle. A broad transcriptional suppression of pro-apoptotic proteins may explain this resistance to lipid-induced cell death in skeletal muscle.

Topics: Animals; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Caspase 3; Dietary Fats; Disease Models, Animal; Down-Regulation; Fat Emulsions, Intravenous; Fatty Acids, Nonesterified; Gene Expression Profiling; Hypertrophy; Leptin; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Atrophy; Obesity; Oligonucleotide Array Sequence Analysis; Proteasome Endopeptidase Complex; Time Factors; Transcription, Genetic

Muscle wasting is a hallmark of uremic cachexia and has frequently been attributed to malnutrition that manifests as anorexia in chronic kidney disease. However, recent evidence indicates that proteolytic mechanisms are responsible for atrophy. Cheung and colleagues have reexamined the links between loss of lean body mass and nutrition. They demonstrate that neuropeptide signaling pathways, which regulate appetite and energy expenditure, also affect expression of key proteins involved in muscle mass maintenance.

Topics: Animals; Appetite Regulation; Cachexia; Chronic Disease; Humans; Leptin; Male; Melanocortins; Mice; Muscle, Skeletal; Muscular Atrophy; Nutritional Requirements; Signal Transduction; Uremia

Physical inactivity is often associated with positive energy balance and fat gain.. We aimed to assess whether energy intake in excess of requirement activates systemic inflammation and antioxidant defenses and accelerates muscle atrophy induced by inactivity.. Nineteen healthy male volunteers were studied before and at the end of 5 wk of bed rest. Subjects were allowed to spontaneously adapt to decreased energy requirement (study A, n = 10) or were provided with an activity-matched diet (study B, n = 9). Groups with higher (HEB) or lower (LEB) energy balance were identified according to median values of inactivity-induced changes in fat mass (DeltaFM, assessed by bioelectrical impedance analysis).. In pooled subjects (n = 19; median DeltaFM: 1.4 kg), bed rest-mediated decreases in fat-free mass (bioelectrical impedance analysis) and vastus lateralis thickness (ultrasound imaging) were significantly greater (P < 0.03) in HEB(AB) (-3.8 +/- 0.4 kg and -0.32 +/- 0.04 cm, respectively) than in LEB(AB) (-2.3 +/- 0.5 kg and -0.09 +/- 0.04 cm, respectively) subjects. In study A (median DeltaFM: 1.8 kg), bed rest-mediated increases in plasma leptin, C-reactive protein, and myeloperoxidase were greater (P < 0.04) in HEB(A) than in LEB(A) subjects. Bed rest-mediated changes of glutathione synthesis rate in eythrocytes (l-[3,3-(2)H(2)]cysteine incorporation) were greater (P = 0.03) in HEB(A) (from 70 +/- 19 to 164 +/- 29%/d) than in LEB(A) (from 103 +/- 23 to 84 +/- 27%/d) subjects.. Positive energy balance during inactivity is associated with greater muscle atrophy and with activation of systemic inflammation and of antioxidant defenses. Optimizing caloric intake may be a useful strategy for mitigating muscle loss during period of chronic inactivity.

Topics: Adipose Tissue; Adult; Bed Rest; Biomarkers; Body Composition; C-Reactive Protein; Electric Impedance; Energy Intake; Energy Metabolism; Erythrocytes; Glutathione; Humans; Inflammation; Leptin; Lipid Metabolism; Male; Muscular Atrophy; Nutritional Requirements; Oxidation-Reduction; Oxidative Stress; Risk Factors; Weight Gain

Insulin-like growth factor (IGF)-I increases muscle mass while myostatin inhibits its development. Muscle wasting is common in patients with uremic cachexia and may be due to imbalance of this regulation. We had proposed a central mechanism involving leptin and melanocortin signaling in the pathogenesis of uremic cachexia since agouti-related peptide (AgRP), a melanocortin-4 receptor antagonist, reduced uremic cachexia. Here we found that injection of AgRP into the cerebral ventricles resulted in a gain of body mass and improved metabolic rate regulation in a mouse model of uremic cachexia. These salutary effects occurred independent of increased protein and calorie intake. Myostatin mRNA and protein concentrations were increased while those of IGF-I were decreased in the skeletal muscle of uremic mice. AgRP treatment partially corrected these uremia-induced changes. Suppressor of cytokine signaling-2 gene expression (SOCS2) was significantly increased in uremic animals and AgRP reduced this expression. We suggest that AgRP improves uremic cachexia and muscle wasting by a peripheral mechanism involving the balance between myostatin and IGF-I.

Topics: Agouti-Related Protein; Animals; Appetite Regulation; Cachexia; Chronic Disease; Gene Expression; Humans; Insulin-Like Growth Factor I; Leptin; Male; Melanocortins; Mice; Mice, Inbred C57BL; Muscular Atrophy; Myostatin; Nephrectomy; RNA, Messenger; Signal Transduction; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Transforming Growth Factor beta; Uremia