Conditioned Media from Head and Neck Cancer Cell Lines and Serum Samples from Head and Neck Cancer Patients Drive Catabolic Pathways in Cultured Muscle Cells.

Background: The role of secreted factors from the tumor cells in driving cancer cachexia and especially muscle loss is unknown. We wanted to study both the action of secreted factors from head and neck cancer (HNC) cell lines and circulating factors in HNC patients on skeletal muscle protein catabolism.

Methods: Conditioned media (CM) made from head and neck cancer cell lines and mix of sera from head and neck cancer (HNC) patients were incubated for 48 h with human myotubes.

Vitamin D status modulates mitochondrial oxidative capacities in skeletal muscle: role in sarcopenia.

Skeletal muscle mitochondrial function is the biggest component of whole-body energy output. Mitochondrial energy production during exercise is impaired in vitamin D-deficient subjects. In cultured myotubes, loss of vitamin D receptor (VDR) function decreases mitochondrial respiration rate and ATP production from oxidative phosphorylation.

Sphingomyelinase activity promotes atrophy and attenuates force in human muscle fibres and is elevated in heart failure patients.

Background: Activation of sphingomyelinase (SMase) as a result of a general inflammatory response has been implicated as a mechanism underlying disease-related loss of skeletal muscle mass and function in several clinical conditions including heart failure. Here, for the first time, we characterize the effects of SMase activity on human muscle fibre contractile function and assess skeletal muscle SMase activity in heart failure patients.

Methods: The effects of SMase on force production and intracellular Ca handling were investigated in single intact human muscle fibres.

Simulation of multi-curve active catheterization for endovascular navigation to complex targets.

The recent development of endovascular therapies has been accompanied by increasingly accurate navigation simulations to assist surgeons in decision making processes or to produce training tools. However, they have been focused mostly on targets within the aortic vasculature. In order to reach complex targets such as cerebral arteries by endovascular navigation, an active guidewire made of a Shape Memory Alloy (SMA) was recently proposed.

Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma.

The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. CDK9 - a component of the transcription elongation complex P-TEFb - bound to the MYCN-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription.

Autophagy flux in critical illness, a translational approach.

Recent clinical trials suggest that early nutritional support might block the induction of autophagy in critically ill patients leading to the development of organ failure. However, the regulation of autophagy, especially by nutrients, in critical illness is largely unclear. The autophagy flux (AF) in relation to critical illness and nutrition was investigated by using an in vitro model of human primary myotubes incubated with serum from critically ill patients (ICU).

Dystrophy-associated caveolin-3 mutations reveal that caveolae couple IL6/STAT3 signaling with mechanosensing in human muscle cells.

Caveolin-3 is the major structural protein of caveolae in muscle. Mutations in the CAV3 gene cause different types of myopathies with altered membrane integrity and repair, expression of muscle proteins, and regulation of signaling pathways. We show here that myotubes from patients bearing the CAV3 P28L and R26Q mutations present a dramatic decrease of caveolae at the plasma membrane, resulting in abnormal response to mechanical stress.

Can exercise and nutrition stimulate muscle protein gain in the ICU patient?

Purpose Of Review: The intended purpose of nutritional and exercise interventions during ICU stay is often to limit the muscle loss associated with critical illness. Unfortunately, direct measurements of muscle protein turnover or potential surrogates have often been neglected in clinical trials.

Recent Findings: We discuss the potential advantages and drawbacks of common outcome measures for assessing changes in muscle structure and function over time, and how temporal changes in patient physiology require consideration.

The caveolae dress code: structure and signaling.

Over the past decade, interest in caveolae biology has peaked. These small bulb-shaped plasma membrane invaginations of 50-80nm diameter present in most cell types have been upgraded from simple membrane structures to a more complex bona fide organelle. However, although caveolae are involved in several essential cellular functions and pathologies, the underlying molecular mechanisms remain poorly defined.

Muscle metabolism.

Purpose Of Review: To review the recent findings on metabolic derangements leading to loss of muscle mass and function.

Recent Findings: Several recent studies investigated methods to assess muscle mass and function and its clinical relevance. These are also included.

Omics and cachexia.

Purpose Of Review: The purpose of this review is to recapture recent advances in cachexia-related diseases, mainly cancer cachexia, and treatment using genomic, transcriptomics, proteomic, and metabolomics-related techniques.

Recent Findings: From recent studies in the cancer cachexia field it is clear that the tumor has a direct effect on distant organs via its secretome. The affected pathways on the other hand were largely known from earlier studies with changes in energy-related pathways (mainly lipid metabolism) and the protein degradation pathways.

Changes in aerobic capacity and glycaemic control in response to reduced-exertion high-intensity interval training (REHIT) are not different between sedentary men and women.

Previously it has been reported that reduced-exertion high-intensity interval training (REHIT; total training time of 3 × 10 min per week) improves maximal aerobic capacity in both sedentary men and women, but improves insulin sensitivity in men only. The aim of the present study was to determine whether there is a true sex difference in response to REHIT, or that these findings can be explained by the large interindividual variability in response inherent to all exercise training. Thirty-five sedentary participants (18 women; mean ± SD age for men and women, respectively: age, 33 ± 9 and 36 ± 9 years; body mass index, 25.

The effect of plasma from septic ICU patients on healthy rat muscle mitochondria.

Background: Although sepsis-induced organ failure is a major cause of death in ICU worldwide, the associated mitochondrial dysfunction is not fully characterized and there is presently no evidence of causality. In this study, we examined whether a central factor in septic plasma could directly affect respiratory function of healthy rat muscle mitochondria.

Methods: ICU patients with severe sepsis or septic shock were recruited within 24 h of admission together with age-matched controls.

Omics/systems biology and cancer cachexia.

Cancer cachexia is a complex syndrome generated by interaction between the host and tumour cells with a background of treatment effects and toxicity. The complexity of the physiological pathways likely involved in cancer cachexia necessitates a holistic view of the relevant biology. Emergent properties are characteristic of complex systems with the result that the end result is more than the sum of its parts.

Optimizing the measurement of mitochondrial protein synthesis in human skeletal muscle.

The measurement of mitochondrial protein synthesis after food ingestion, contractile activity, and/or disease is often used to provide insight into skeletal muscle adaptations that occur in the longer term. Studies have shown that protein ingestion stimulates mitochondrial protein synthesis in human skeletal muscle. Minor differences in the stimulation of mitochondrial protein synthesis occur after a single bout of resistance or endurance exercise.

Muscle ectopic fat deposition contributes to anabolic resistance in obese sarcopenic old rats through eIF2α activation.

Obesity and aging are characterized by decreased insulin sensitivity (IS) and muscle protein synthesis. Intramuscular ceramide accumulation has been implicated in insulin resistance during obesity. We aimed to measure IS, muscle ceramide level, protein synthesis, and activation of intracellular signaling pathways involved in translation initiation in male Wistar young (YR, 6-month) and old (OR, 25-month) rats receiving a low- (LFD) or a high-fat diet (HFD) for 10 weeks.

Autophagic-lysosomal pathway is the main proteolytic system modified in the skeletal muscle of esophageal cancer patients.

Background: In cancer cachexia, muscle depletion is related to morbidity and mortality. Muscle-wasting mechanisms in cancer patients are not fully understood.

Objective: We investigated the involvement of the proteolytic systems (proteasome, autophagic-lysosomal, calpain, and caspase) in muscle wasting during cancer cachexia.

¹H NMR and hyperpolarized ¹³C NMR assays of pyruvate-lactate: a comparative study.

Pyruvate-lactate exchange is mediated by the enzyme lactate dehydrogenase (LDH) and is central to the altered energy metabolism in cancer cells. The measurement of exchange kinetics using hyperpolarized (13) C NMR has provided a biomarker of response to novel therapeutics. However, the observable signal is restricted to the exchanging hyperpolarized (13) C pools and the endogenous pools of (12) C-labelled metabolites are invisible in these measurements.

TNFα gene knockout differentially affects lipid deposition in liver and skeletal muscle of high-fat-diet mice.

Aims/hypothesis: Inflammation and ectopic lipid deposition contribute to obesity-related insulin resistance (IR). Studies have shown that deficiency of the proinflammatory cytokine tumor necrosis factor-α (TNFα) protects against the IR induced by a high-fat diet (HFD). We aimed to evaluate the relationship between HFD-related inflammation and lipid deposition in skeletal muscle and liver.

Cumulative 3-nitrotyrosine in specific muscle proteins is associated with muscle loss during aging.

Post-translational oxidative protein modifications which are more marked during aging and/or high-calorie (HC) diets affect protein function and metabolism. Protein function and metabolism are different according to the type of muscle proteins. Oxidative muscle protein modifications may thus be associated with age-related sarcopenia, and HC may be implicated in the development of sarcopenia by emphasizing protein modifications.

Oleate-enriched diet improves insulin sensitivity and restores muscle protein synthesis in old rats.

Background & Aims: Age-related inflammation and insulin resistance (IR) have been implicated in the inability of old muscles to properly respond to anabolic stimuli such as amino acids (AA) or insulin. Since fatty acids can modulate inflammation and IR in muscle cells, we investigated the effect of palmitate-enriched diet and oleate-enriched diet on inflammation, IR and muscle protein synthesis (MPS) rate in old rats.

Methods: Twenty-four 25-month-old rats were fed either a control diet (OC), an oleate-enriched diet (HFO) or a palmitate-enriched diet (HFP) for 16 weeks.