Loss Of Skeletal Muscle Protein Research Articles

Increased Expression of MiRNA-1 Contributes to Hypobaric Hypoxia-Induced Skeletal Muscle Loss.

The present study aims to analyze the role of microRNA-1 in the regulation of skeletal muscle loss under hypobaric hypoxia (HH). Male Sprague Dawley rats (n = 10) weighing 230-250g are divided into two groups, control and HH exposure for 7 days at 25000ft. After the hypoxia exposure, the animals are sacrificed and hindlimb skeletal muscles are excised for further analysis. Studies found the potential role of miR-1 (myomiR) as a biomarker under different atrophic conditions. Prolonged exposure to HH leads to enhanced expression of miR-1 in skeletal muscle as compared to unexposed controls. The Bioinformatics approach is used to identify the validated targets and the biological processes of miR-1. The target prediction tools identify PAX3 and HSP70 as major targets for miR-1. Exposure to HH significantly reduces PAX3 and HSP70 expression during 7 days of HH exposure, which further enhances the activity of FOXO3, MSTN, and ATROGIN known for the progression of skeletal muscle atrophy in relation to control rats. This study indicates the increased expressions of miR-1 and reduced expression of PAX3 and HSP70 lead to impaired myogenesis in skeletal muscle under HH. Further, enhanced expression of muscle degradation genes such as FOXO3, MSTN, and ATROGIN under HH exposure causes skeletal muscle protein loss.

Perioperative amino acid infusion reestablishes muscle net balance during total hip arthroplasty.

Surgery and anesthesia induce a catabolic response that leads to skeletal muscle protein loss. Previous investigations have observed positive effects of perioperative nutrition. Furthermore, the benefits of exogenous amino acids on muscle protein kinetics are well established. However, no investigation has focused on muscle protein kinetics with and without perioperative amino acid infusion. Thus, we aimed to assess the effect of perioperative amino acid (AA) infusion on muscle protein balance in individuals undergoing elective total hip arthroplasty (THA). Elective THA patients were randomized to undergo a metabolic study prior to surgery (n = 5; control [CON]), intraoperative AA infusion (n = 9), or no AA (n = 13; standard of care [SC]). The CON group was studied prior to surgery to provide nonoperative/non‐anesthesia muscle protein kinetic reference values. The bolus infusion method with 13C6‐phenylalanine injected at time 0, and [15N]‐phenylalanine 30 min later was used to calculate muscle protein synthesis (MPS), protein breakdown (MPB), and net balance (MPS−MPB). Perioperative AA significantly improved muscle net balance as compared to SC (−0.005 ± 0.018%/h vs. −0.052 ± 0.011%/h) but not CON (0.003 ± 0.013%/h). The AA infusion significantly increased muscle net balance via a significant increase in MPS (AA = 0.062 ± 0.007%/h; SC = 0.037 ± 0.004%/h; CON = 0.072% ± 0.005%/h), and a nonsignificant attenuation of MPB (AA = 0.067 ± 0.012%/h; SC = 0.089 ± 0.014%/h; CON = 0.075 ± 0.011%/h). Our data support the use of perioperative AA infusion during elective THA as pragmatic strategy to offset the loss of surgically induced skeletal muscle protein.

Endogenous dipeptide-carnosine supplementation ameliorates hypobaric hypoxia-induced skeletal muscle loss via attenuating endoplasmic reticulum stress response and maintaining proteostasis.

High altitude is an environmental stress that is accompanied with numerous adverse biological responses, including skeletal muscle weakness and muscle protein loss. Skeletal muscle wasting is an important clinical problem, progressing to critical illness, associated with increased morbidity and mortality. The present study explores the protective efficacy of endogenous dipeptide, carnosine (CAR), supplementation in ameliorating skeletal muscle protein loss under hypobaric hypoxia (HH). Male Sprague-Dawley rats (n=5) were randomly divided into control group, HH-exposed group (3 days HH exposure equivalent to 7,620 m), and HH-exposed rats supplemented with carnosine (3 days; 150 mg/kg b.w, orally) (HH + CAR). HH-exposed rats supplemented with CAR ameliorated HH-induced oxidative protein damage, lipid peroxidation, and maintained pro-inflammatory cytokines levels. HH-associated muscle protein degradative pathways, including calpain, ubiquitination, endoplasmic reticulum stress, autophagy, and apoptosis were also regulated in carnosine-supplemented rats. Further, the muscle damage marker, the levels of serum creatine phosphokinase were also reduced in HH + CAR co-supplemented rats which proved the protective efficacy of CAR against hypobaric hypoxia-induced muscle protein loss. Altogether, CAR supplementation ameliorated HH-induced skeletal muscle protein loss via performing multifaceted ways, mainly by maintaining redox homeostasis and proteostasis in skeletal muscle.

Ursolic acid ameliorates hypobaric hypoxia-induced skeletal muscle protein loss via upregulating Akt pathway: An experimental study using rat model.

Hypobaric hypoxic stress leads to oxidative stress, inflammation, and disturbance in protein turnover rate. Aggregately, this imbalance in redox homeostasis is responsible for skeletal muscle protein loss and a decline in physical performance. Hence, an urgent medical need is required to ameliorate skeletal muscle protein loss. The present study investigated the efficacy of ursolic acid (UA), a pentacyclic triterpene acid to ameliorate hypobaric hypoxia (HH)-induced muscle protein loss. UA is a naturally occurring pentacyclic triterpene acid present in several edible herbs and fruits such as apples. It contains skeletal muscle hypertrophy activity; still its potential against HH-induced muscle protein loss is unexplored. To address this issue, an in vivo study was planned to examine the beneficial effect of UA supplementation on HH-induced skeletal muscle loss. Male Sprague Dawley rats were exposed to HH with and without UA supplementation (20 mg/kg; oral) for 3 continuous days. The results described the beneficial role of UA as supplementation of UA with HH exposure attenuated reactive oxygen species production and oxidative protein damage, which indicate the potent antioxidant activity. Furthermore, UA supplementation enhanced Akt, pAkt, and p70S6kinase activity (Akt pathway) and lowered the pro-inflammatory cytokines in HH exposed rats. UA has potent antioxidant and anti-inflammatory activity, and it enhanced the protein content via upregulation of Akt pathway-related proteins against HH exposure. These three biological activities of UA make it a novel candidate for amelioration of HH-induced skeletal muscle damage and protein loss.

OR-017 Supplementation of Ala-Gln inhibits protein breakdown of skeletal muscle in rats with altitude training through TNF-α/NF-κB/MuRF1 pathway

Objective Objective: To explore the effects of alanyl-glutamine（Ala-Gln）or glutamine（Gln） supplementation on protein metabolism in rat skeletal muscle during simulated altitude training，and compare the intervention of Gln or Ala-Gln to provide the necessary experimental basis for finding nutritional interventions to inhibit skeletal muscle protein degradation during altitude training.
 Methods Methods: Forty SD rats aged 6 weeks were randomly divided into normoxic control group（NC group，n=10），hypoxic exercise group（HE group， n=10），hypoxic exercise + glutamine + alanine group（HEG group，n=10）， hypoxic exercise + alanyl glutamine group（HEAG group，n=10）. Rats were subjected to 6 weeks of 13.6% hypoxic exposure and 90% lactic acid threshold intensity weight-bearing swimming（load weight of 2.1% of body weight）exercise training，30 minutes after the end of each training，the mixed solution of Ala and Gln was administered according to the dose of 0.75g/Kg body weight in HEG group，and the solution of Ala-Gln was administered in the HEAG group at a dose of 1.5 g/kg body weight. After 6 weeks，the contents of rat skeletal muscle total protein（Pro），myosin heavy chain（Myo），tumor necrosis factor-α（TNF-α），nuclear transcription factor-κB （NF-κB），NF-κB inhibitory protein α（IkBα），and mRNA expression of muscle atrophy box F gene（MAFbx），muscle ring finger gene 1（MuRF1），and inhibitor of kappa B kinase complex-beta（IKKβ）were measured.
 Results Results:（1）Compared with NC group，the content of Pro and Myo in skeletal muscle in HE group was significantly decreased（P<0.05，P<0.01），and the mRNA expression of MAFbx and MuRF1 in skeletal muscle was significantly increased（P<0.05，P< 0.01），the levels of TNF-α and NF-κB were significantly increased（P<0.05），the content of IkBα was significantly decreased（P<0.05），and the expression of IKKβ mRNA was significantly increased（P<0.01）. （2）Compared with HE group，the content of Pro and Myo in skeletal muscle in HEG group increased，but there was no significant difference（P>0.05）. The expression of MuRF1 mRNA and the content of TNF-α and NF-κB in skeletal muscle decreased，IkBα content increased，there were no significant difference，but mRNA expression of MAFbx and IKKβ was significantly decreased（P<0.05， P<0.01）. （3）Compared with HE group，the content of Pro and Myo in skeletal muscle in HEAG group increased significantly（P<0.05），mRNA expression of IKKβ，MuRF1 and MAFb（P<0.01）and TNF-α，NF-κB content（P<0.05）in skeletal muscle was significantly decreased，and the IkBα content was significantly increased（P<0.05）.
 Conclusions Conclusion:（1）Simulated altitude training can activate TNF-α/NF-κB/MuRF1 pathway and enhance the catabolism of skeletal muscle protein，which is one of the important mechanisms for the reduction of skeletal muscle protein content caused by altitude training. （2）Supplementation of Ala-Gln during altitude training can significantly reduce the activation of TNF-α/NF-κB/MuRF1 pathway in skeletal muscle，and reduce the catabolism of skeletal muscle protein during altitude training，which plays a very important role in preventing the loss of skeletal muscle protein caused by altitude training. supplementation of Gln monomer during altitude training has little inhibitory effect on the activation of TNF-α/NF-κB/MuRF1 pathway in skeletal muscle.

Sarcopenia and Exercise “The State of the Art”

Skeletal muscle mass reduction might be a consequence of aging (sarcopenia), disease (cachexia) or inactivity (muscle atrophy). Studying the triggering factors leading to muscle loss is important in developing therapies to preserve muscle tissue function. The loss of skeletal muscle proteins is caused by an imbalance between the rate of their synthesis and degradation. Specifically, the conditions characterized by muscle loss involve an adaptation metabolism of increased protein degradation (cachexia), decreased muscle protein synthesis (inactivity), or alteration in both (sarcopenia). Sarcopenia and exercise is the main topic chosen for this review. This is a huge health problem, poorly discussed in the current literature and the aim of this review is to explain and help readers to better understand the differences between “sarcopenia”, “cachexia”, “muscle atrophy” and the relative beneficial effects of exercise used as a possible therapeutic intervention. Sarcopenia is a component of the fragility syndrome and indicates a significant health issue related to the progressive decline of muscle tissue quality and strength. Exercise is associated with improved life quality, reduced health problems, and prolonged lifespan. The latter suggests that exercise should be considered a fundamental point in the treatment of pathological skeletal muscle mass reduction. The present scientific contribution also seeks to emphasize to the scientific community the positive effects of the adapted physical activity in the elderly as a possible non-pharmacologic treatment to prevent or treat muscle atrophy.

Skeletal muscle mass and composition during mammalian hibernation.

Hibernation is characterized by prolonged periods of inactivity with concomitantly low nutrient intake, conditions that would typically result in muscle atrophy combined with a loss of oxidative fibers. Yet, hibernators consistently emerge from winter with very little atrophy, frequently accompanied by a slight shift in fiber ratios to more oxidative fiber types. Preservation of muscle morphology is combined with down-regulation of glycolytic pathways and increased reliance on lipid metabolism instead. Furthermore, while rates of protein synthesis are reduced during hibernation, balance is maintained by correspondingly low rates of protein degradation. Proposed mechanisms include a number of signaling pathways and transcription factors that lead to increased oxidative fiber expression, enhanced protein synthesis and reduced protein degradation, ultimately resulting in minimal loss of skeletal muscle protein and oxidative capacity. The functional significance of these outcomes is maintenance of skeletal muscle strength and fatigue resistance, which enables hibernating animals to resume active behaviors such as predator avoidance, foraging and mating immediately following terminal arousal in the spring.

Contributions to the understanding of the anabolic properties of different dietary proteins

Contributions to the understanding of the anabolic properties of different dietary proteins

Neuromuscular electrical stimulation increases muscle protein synthesis rates in type 2 diabetic men

A loss of skeletal muscle proteins ultimately lowers the capacity for blood glucose disposal. Thus, the development of paradigms that can increase muscle protein accretion will have implications for the treatment of type 2 diabetes at a more advanced age. We aimed to determine the effect of neuromuscular electrical stimulation (NMES) on mixed muscle protein synthesis rates in type 2 diabetic men. Six sedentary, type 2 diabetic men (Age: 70±1 y, BMI: 26.5±1.0 kg·m−2) received a primed, constant infusion of L‐[ring‐13C6]phenylalanine and 60 min of one legged NMES. Biopsies of the vastus lateralis were obtained at 0, 2, and 4 h after NMES to measure mixed muscle protein synthesis rates in the unstimulated (CON) and stimulated (STIM) leg. The electrical current of the NMES protocol consisted of a pulse duration of 500 μs, pulse frequency of 60 Hz, and a 3 sec contraction – 3 sec relaxation time. Muscle protein synthesis rates were increased by 21% and 64% above CON at 0–2 h and 2–4 h in the STIM leg, respectively (P<0.05). Similarly, the cumulative MPS response (0–4 h) was greater in the STIM (0.049±0.008 %·h−1) compared with the CON leg (0.039±0.008 %·h−1). Our data demonstrate that NMES stimulates mixed muscle protein synthesis rates in vivo in humans. This work lends credence to the use of NMES to attenuate muscle protein loss during periods of muscle disuse or to support an increase in skeletal muscle hypertrophy.

Metabolic Signatures Imaged in Cancer-Induced Cachexia

Cancer-induced cachexia is a complex and poorly understood life-threatening syndrome that is characterized by progressive weight loss due to metabolic alterations, depletion of lipid stores, and severe loss of skeletal muscle protein. Gaining the ability to noninvasively image the presence or onset of cachexia is important to better treat this condition, to improve the design and optimization of therapeutic strategies, and to detect the responses to such treatments. In this study, we employed noninvasive magnetic resonance spectroscopic imaging (MRSI) and [(18)F]fluoro-2-deoxy-D-glucose ((18)FDG) positron emission tomography (PET) to identify metabolic signatures typical of cachectic tumors, using this information to analyze the types and extents of metabolic changes induced by the onset of cachexia in normal tissues. Cachexia was confirmed by weight loss as well as analyses of muscle tissue and serum. In vivo, cachexia-inducing murine adenocarcinoma (MAC)16 tumors were characterized by higher total choline (tCho) and higher (18)FDG uptake than histologically similar noncachectic MAC13 tumors. A profound depletion of the lipid signal was observed in normal tissue of MAC16 tumor-bearing mice but not within the tumor tissue itself. High-resolution (1)H magnetic resonance spectroscopy (MRS) confirmed the high tCho level observed in cachectic tumors that occurred because of an increase of free choline and phosphocholine. Higher succinate and lower creatine levels were also detected in cachectic tumors. Taken together, these findings enhance our understanding of the effect of cancer on host organs and tissues as well as promote the development of noninvasive biomarkers for the presence of cachexia and identification of new therapeutic targets.

Decreased NADPH oxidase expression and antioxidant activity in cachectic skeletal muscle

BackgroundCancer cachexia is the progressive loss of skeletal muscle protein that contributes significantly to cancer morbidity and mortality. Evidence of antioxidant attenuation and the presence of oxidised proteins in patients with cancer cachexia indicate a role for oxidative stress. The level of oxidative stress in tissues is determined by an imbalance between reactive oxygen species production and antioxidant activity. This study aimed to investigate the superoxide generating NADPH oxidase (NOX) enzyme and antioxidant enzyme systems in murine adenocarcinoma tumour-bearing cachectic mice.MethodsSuperoxide levels, mRNA levels of NOX enzyme subunits and the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidise (GPx) and catalase was measured in the skeletal muscle of mice with cancer and cancer cachexia. Protein expression levels of NOX enzyme subunits and antioxidant enzyme activity was also measured in the same muscle samples.ResultsSuperoxide levels increased 1.4-fold in the muscle of mice with cancer cachexia, and this was associated with a decrease in mRNA of NOX enzyme subunits, NOX2, p40phox and p67phox along with the antioxidant enzymes SOD1, SOD2 and GPx. Cancer cachexia was also associated with a 1.3-fold decrease in SOD1 and 2.0-fold decrease in GPx enzyme activity.ConclusionDespite increased superoxide levels in cachectic skeletal muscle, NOX enzyme subunits, NOX2, p40phox and p67phox, were downregulated along with the expression and activity of the antioxidant enzymes. Therefore, the increased superoxide levels in cachectic skeletal muscle may be attributed to the reduction in the activity of endogenous antioxidant enzymes.

Combined approach to counteract experimental cancer cachexia: eicosapentaenoic acid and training exercise

BackgroundCancer cachexia is a syndrome characterized by loss of skeletal muscle protein, depletion of lipid stores, anorexia, weakness, and perturbations of the hormonal homeostasis. Despite several therapeutic approaches described in the past, effective interventions countering cancer cachexia are still lacking.MethodsThe present work was aimed to verify the ability of eicosapentaenoic acid (EPA) to prevent the muscle depletion in Lewis lung carcinoma-bearing mice and to test the ability of endurance exercise training to increase the EPA effect.ResultsEPA alone did not prevent the muscle loss induced by tumor growth while the combination with exercise induced a partial rescue of muscle strength and mass. Moreover, the association of EPA and exercise reduced the dramatic PAX-7 accumulation and stimulated the increase of PCG-1 protein.ConclusionsOverall, the present data suggest that exercise is an effective tool that should be added for combined therapeutic approaches against cancer cachexia.Electronic supplementary materialThe online version of this article (doi:10.1007/s13539-011-0028-4) contains supplementary material, which is available to authorized users.

STZ-induced skeletal muscle atrophy is associated with increased p65 content and downregulation of insulin pathway without NF-κB canonical cascade activation

Type 1 diabetes mellitus (DM)-induced skeletal muscle atrophy is associated with an increased incidence in morbidity and mortality. Although the precise mechanism of diabetes-induced skeletal muscle atrophy remains to be established, several NF-κB-dependent pro-inflammatory genes have been identified as potential therapeutic targets. Moreover, activation of NF-κB has previously been shown to be required for cytokine-induced loss of skeletal muscle proteins. Therefore, we investigated activation of the NF-κB canonical pathway, concomitant to insulin signaling activation in skeletal muscle from diabetes-induced rats. Ten rats injected with streptozotocin (STZ) 4 weeks prior to tissue extraction were compared to 10 control rats. Using total, cytosolic and nuclear protein extracts from hindlimb muscles: soleus (SOL), extensor digitorum longus (EDL), gastrocnemius (GM) and liver tissue, we assessed key proteins important for the activation of both NF-κB and insulin pathways. Insulin blood concentration decreased to 3.9 ± 1.2 mU/ml following STZ-injection resulting in hyperglycemia (17.9 ± 0.7 mmol/l). SOL, EDL and GM mass decreased, and liver mass increased following STZ injection. NF-κB/p65 content in SOL, GM and liver increased in STZ-injected rats, without any change in IκB degradation or IKK phosphorylation. Muscle NF-κB/p65 remained bound to IκB and did not translocate or bind to DNA. Although the canonical NF-κB cascade was not activated, STZ induced a decrease in insulin pathway proteins including insulin receptor (IR) and substrate (IRS-1) content and phosphorylation compared to control animals. A downregulation of insulin pathway proteins and muscle atrophy occurred in response to STZ administration, and despite increased p65 content, STZ treatment did not activate the canonical NF-κB cascade. Therefore, it is unlikely that hyperglycemia initiates skeletal muscle atrophy via activation of the NF-κB canonical pathway.

Skeletal muscle: Increasing the size of the locomotor cell

Skeletal muscle is the most abundant tissue in the body comprising 40–50% of body mass in humans and playing a central role in maintaining metabolic health. Skeletal muscle protein undergoes rapid turnover, a process that is intricately regulated by the balance between the rates of protein synthesis and degradation. The process of skeletal muscle hypertrophy and regeneration is an important adaptive response to both contractile activity (i.e., exercise) and nutrient availability (i.e., protein ingestion). Ageing and physical inactivity are two conditions associated with a loss of skeletal muscle protein (sarcopenia). Sarcopenia is characterised by a deterioration of muscle quantity and quality, although the precise mechanism(s) underlying this condition remain to be elucidated. This review will (1) summarise our current understanding of the origin and plasticity of skeletal muscle, (2) discuss the major effectors of muscle growth, and (3) highlight the importance of skeletal muscle health in the prevention of several common pathologies.

Mitochondrial fission and remodelling contributes to muscle atrophy

Mitochondria are crucial organelles in the production of energy and in the control of signalling cascades. A machinery of pro-fusion and fission proteins regulates their morphology and subcellular localization. In muscle this results in an orderly pattern of intermyofibrillar and subsarcolemmal mitochondria. Muscular atrophy is a genetically controlled process involving the activation of the autophagy-lysosome and the ubiquitin-proteasome systems. Whether and how the mitochondria are involved in muscular atrophy is unknown. Here, we show that the mitochondria are removed through autophagy system and that changes in mitochondrial network occur in atrophying muscles. Expression of the fission machinery is per se sufficient to cause muscle wasting in adult animals, by triggering organelle dysfunction and AMPK activation. Conversely, inhibition of the mitochondrial fission inhibits muscle loss during fasting and after FoxO3 overexpression. Mitochondrial-dependent muscle atrophy requires AMPK activation as inhibition of AMPK restores muscle size in myofibres with altered mitochondria. Thus, disruption of the mitochondrial network is an essential amplificatory loop of the muscular atrophy programme.

Skeletal muscle loss: cachexia, sarcopenia, and inactivity

Loss of skeletal muscle mass occurs during aging (sarcopenia), disease (cachexia), or inactivity (atrophy). This article contrasts and compares the metabolic causes of loss of muscle resulting from these conditions. An understanding of the underlying causes of muscle loss is critical for the development of strategies and therapies to preserve muscle mass and function. Loss of skeletal muscle protein results from an imbalance between the rate of muscle protein synthesis and degradation. Cachexia, sarcopenia, and atrophy due to inactivity are characterized by a loss of muscle mass. Each of these conditions results in a metabolic adaptation of increased protein degradation (cachexia), decreased rate of muscle protein synthesis (inactivity), or an alteration in both (sarcopenia). The clinical consequences of bedrest may mimic those of cachexia, including rapid loss of muscle, insulin resistance, and weakness. Prophylaxis against bedrest-induced atrophy includes nutrition support with an emphasis on high-quality protein. Nutritional supplementation alone may not prevent muscle loss secondary to cachexia, but, in combination with the use of an anabolic agent, it may slow or prevent muscle loss.

Doxorubicin stimulates catabolism in C2C12 myotubes

Doxorubicin, a commonly prescribed chemotherapeutic agent, causes skeletal muscle wasting in cancer patients undergoing chemotherapy. Previous studies in mice show that the E3 ubiquitin ligase, MAFbx/atrogin‐1 is upregulated in skeletal muscle following doxorubicin administration, an effect regulated by p38 MAPK signaling. Activation of p38 MAPK also promotes caspase‐3 activation. These findings led us to hypothesize that doxorubicin causes skeletal muscle atrophy through p38 MAPK signaling, leading to the upregulation of MAFbx/atrogin‐1 and caspase‐3. We measured the loss of myofibrillar proteins in C2C12 myotubes exposed to doxorubicin (0.2 μM, 48 hrs). Compared to control, actin (mean ± SE; −49 ± 4 %, n=3, p<0.01) and myosin (−40 ± 9 %, n=11, p<0.05) proteins decreased. p38 MAPK phosphorylation was elevated in 30 mins following doxorubicin exposure (16 ± 3 %, n=6, p<0.05). Doxorubicin increased MAFbx/atrogin‐1 mRNA 16 hrs (74 ± 8%, n=3, p<0.01) and 24 hrs (132 ± 8 %, n=3, p<0.01) following exposure. Caspase‐3, both precursor and active form, were elevated 6 hrs (precursor: 25 ± 7 %, n=3, p<0.05; active: 125 ± 35 %, n=3) and 24 hrs (precursor: 36 ± 6, n=3, p<0.01; active: 87 ± 12 %, n=3, p<0.01) following doxorubicin. Our data shows that doxorubicin causes skeletal muscle protein loss, which may be mediated through p38 MAPK signaling and upregulation of MAFbx/atrogin‐1 and caspase‐3.Supported by: T32 HL086341‐02 (EWP) and AHA predoctoral fellowship(LAAG)

Daily brief restraint stress alters signaling pathways and induces atrophy and apoptosis in rat skeletal muscle

Skeletal muscle protein loss, known as atrophy, occurs during inactivity, disease, and aging. Atrophy may be the result of increased catabolic factors, e.g. glucocorticoids, or reduced influence of anabolic factors, e.g. insulin. The purpose of this study was to investigate atrophy, signaling mechanisms, and apoptosis in a rat model of restraint stress in 40 adult male Wistar rats. Due to the anxiolytic effects of Sutherlandia frutescens, we also determined if any of the molecular events in gastrocnemius muscle would be affected by daily treatment with S. frutescens. Rats were randomly assigned to four experimental groups: control placebo (CP); control Sutherlandia (CS) treatment; Restraint Placebo (RP) and Restraint Sutherlandia (RS) treatment. Restraint resulted in a significant increase in myostatin which was significantly reduced with Sutherlandia treatment. In addition, MyoD expression was significantly attenuated in RP and this effect was also counteracted by Sutherlandia treatment. Restraint also resulted in a significant attenuation of the PI3-Kinase/Akt signaling pathway and increased apoptosis which was reversed with Sutherlandia treatment. This study demonstrates for the first time that psychological stress elevates markers of muscle atrophy and apoptosis, whilst a herbal remedy, Sutherlandia, inhibits apoptosis, and signaling pathways associated with muscle atrophy.

Pro-inflammatory cytokines and oxidative stress/antioxidant parameters characterize the bio-humoral profile of early cachexia in lung cancer patients

Cancer-related cachexia, that is present in about 50% of cancer patients and accounts for 20% of all cancer deaths, is clinically characterized by progressive weight loss, anorexia, metabolic alterations, asthenia, depletion of lipid stores and severe loss of skeletal muscle proteins. The main biochemical and molecular alterations that are responsible for the syndrome are prematurely present in the progress of the disease and the identification of the early stages of cachexia can be useful in targetting patients who will benefit from early treatment. The aim of the present study was to delineate the bio-humoral profile of a group of lung cancer patients either non-cachectic or cachectic by evaluating serum pro-inflammatory cytokines and oxidative stress/antioxidant parameters (both recognized to be involved in cachexia pathogenesis) and pro-inflammatory cytokine gene expression in PBMC (Peripheral blood mononuclear cells) of cancer patients. All serum pro-inflammatory cytokines and oxidative stress/antioxidant parameters significantly increased in neoplastic patients, but only TNF-alpha, ROS, GSH and vitamin E showed a significantly greater increase in cachectic patients. Pro-inflammatory cytokine gene expression mirrored serum level behaviour except for IL-6 that was increased in serum but not as gene expression, suggesting its provenience from tumour tissue. Our data support that the simultaneous determination of ROS, GSH, vitamin E, together with TNF-alpha allows the identification of a lung cancer patient developing cancer-related cachexia. This bio-humoral profile should be used for the early diagnosis and follow-up of the syndrome. Moreover, the evaluation of gene expression in patient PBMC was helpful in differentiating tumour vs host factors, therefore being useful in the study of pathogenetic mechanisms in neoplastic cachectic patients.

Inactivity and hormonal deregulation increase human skeletal muscle protein loss

We sought to quantify changes in human skeletal muscle protein kinetics during prolonged inactivity with and without accompanying hypercortisolemia. Oral hydrocortisone sodium succinate (~22 μg/dL) was administered to an experimental group (EXP: male, n=6, 28± 2 y; 84±4 kg; 178± 3 cm;) throughout 28 days of bedrest. The control group (CON: male, n=6; 38±8 y; 86±10 kg; 179±3 cm) received no exogenous cortisol (~10 μg/dL). Femoral arterio-venous blood samples and a vastus lateralis muscle biopsy were obtained during a primed constant infusion of L-[ring-2H5] phenylalanine before and after bed rest. Postabsorptive net balance became more negative in the EXP group following bedrest, a change largely facilitated by a ~40% reduction in protein synthesis in the EXP group. Table 1.. 3-pool model data representing protein synthesis (Fom) and breakdown (Fmo) (nmol/min/100mL leg) before and after bedrest. A similar superscript represents a statistical difference (p<0.05). The EXP group experienced a decrease in plasma testosterone (Day 1: 503.5±56.3 vs. Day 28: 409.5±28.6 ng/dL) and sex hormone binding globulin (SHBG) (Day 1: 22.5±2.5 vs. 12.2±1.5 nmol/L), (p<0.05). This was consistent with 3-fold greater loss of lean leg mass (LLM) in the EXP group (EXP: −1.4±0.1 vs. CON: −0.4±0.1 kg), (p<0.05). In conclusion, a combination of inactivity and hypercortisolemia leads to hormonal deregulation which in-turn further exacerbates muscle protein catabolism. Supported by funding from NPFR00205.