BackgroundCancer cachexia negatively impacts cancer‐related treatment options, quality of life, morbidity, and mortality, yet no established therapies exist. We investigated the anabolic properties of testosterone to limit the loss of body mass in late stage cancer patients undergoing standard of care cancer treatment.MethodsA randomized, double‐blind, placebo‐controlled phase II clinical trial was undertaken to assess the potential therapeutic role of adjunct testosterone to limit loss of body mass in patients with squamous cell carcinoma of the cervix or head and neck undergoing standard of care treatment including chemotherapy and chemoradiation. Patients were randomly assigned in blocks to receive weekly injections of either 100 mg testosterone enanthate or placebo for 7 weeks. The primary outcome was per cent change in lean body mass, and secondary outcomes included assessment of quality of life, tests of physical performance, muscle strength, daily activity levels, resting energy expenditure, nutritional intake, and overall survival.ResultsA total of 28 patients were enrolled, 22 patients were studied to completion, and 21 patients were included in the final analysis (12 placebo, nine testosterone). Adjunct testosterone increased lean body mass by 3.2% (95% confidence interval [CI], 0–7%) whereas those receiving placebo lost 3.3% (95% CI, −7% to 1%, P = 0.015). Although testosterone patients maintained more favourable body condition, sustained daily activity levels, and showed meaningful improvements in quality of life and physical performance, overall survival was similar in both treatment groups.ConclusionsIn patients with advanced cancer undergoing the early phase of standard of care therapy, adjunct testosterone improved lean body mass and was also associated with increased quality of life, and physical activity compared with placebo.

Patients with chronic traumatic brain injury (TBI) requiring long-term, permanent care suffer a myriad of clinical symptoms (i.e., impaired cognition, fatigue, and other conditions) that persist for years beyond the acute brain injury. In addition to these comorbid clinical symptoms, chronic TBI patients exhibit altered amino acid and hormonal profiles with distinct cytokine patterns suggesting chronic inflammation. This metabolic link suggests a role of the gut-brain axis in chronic TBI. Thus, we utilized a two-site trial to investigate the role of the gut-brain axis in comorbidities of chronic TBI. The fecal microbiome profile of 22 moderate/severe TBI patients residing in permanent care facilities in Texas and California was compared to 18 healthy age-matched control subjects working within the participating facilities. Each fecal microbiome was characterized by 16S(V4) ribosomal RNA (rRNA) gene sequencing and metagenomic genome sequencing approaches followed by confirmatory full 16S rRNA gene sequencing or focused tuf gene speciation and specific quantitative polymerase chain reaction evaluation of selected genera or species. The average chronic TBI patient fecal microbiome structure was significantly different compared to the control cohort, and these differences persisted after group stratification analysis to identify any unexpected confounders. Notably, the fecal microbiome of the chronic TBI cohort had absent or reduced Prevotella spp. and Bacteroidies spp. Conversely, bacteria in the Ruminococcaceae family were higher in abundance in TBI compared to control profiles. Previously reported hypoaminoacidemia, including significantly reduced levels of l-tryptophan, l-sarcosine, ß-alanine, and alanine, positively correlated with the reduced levels of Prevotella spp. in the TBI cohort samples compared to controls. Although the sequelae of gut-brain axis disruption after TBI is not fully understood, characterizing TBI-related alterations in the fecal microbiome may provide biomarkers and therapeutic targets to address patient morbidity.

Glucocorticoids (GC) are a frontline therapy for numerous acute and chronic diseases because of their demonstrated efficacy at reducing systemic inflammation. An unintended side effect of GC therapy is the stimulation of skeletal muscle atrophy. Pathophysiological mechanisms responsible for GC‐induced skeletal muscle atrophy have been extensively investigated, and the ability to treat patients with GC without unintended muscle atrophy has yet to be realized. We have reported that a single, standard‐of‐care dose of Methylprednisolone increases in vivo expression of NF‐κB‐inducing kinase (NIK), an important upstream regulatory kinase controlling NF‐κB activation, along with other key muscle catabolic regulators such as Atrogin‐1 and MuRF1 that induce skeletal muscle proteolysis. Here, we provide experimental evidence that overexpressing NIK by intramuscular injection of recombinant human NIK via adenoviral vector in mouse tibialis anterior muscle induces a 30% decrease in the average fiber cross‐sectional area that is associated with increases in mRNA expression of skeletal muscle atrophy biomarkers MuRF1, Atrogin‐1, myostatin and Gadd45. A single injection of GC induced NIK mRNA and protein within 2 h, with the increased NIK localized to nuclear and sarcolemmal locations within muscle fibers. Daily GC injections induced skeletal muscle fore limb weakness as early as 3 days with similar atrophy of muscle fibers as observed with NIK overexpression. NIK overexpression in primary human skeletal muscle myotubes increased skeletal muscle atrophy biomarkers, while NIK knockdown significantly attenuated GC‐induced increases in NIK and Atrogin‐1. These results suggest that NIK may be a novel, previously unrecognized mediator of GC‐induced skeletal muscle atrophy.

Recent studies have suggested myoglobin (Mb) may have other cellular functions in addition to storing and transporting O. Indeed, NMR experiments have shown that the saturated fatty acid (FA) palmitate (PA) can interact with myoglobin (Mb) in its ligated state (MbCO and MbCN) but does not interact with Mb in its deoxygenated state. The observation has led to the hypothesis that Mb can also serve as a fatty acid transporter. The present study further investigates fatty acid interaction with the physiological states of Mb using the more soluble but unsaturated fatty acid, oleic acid (OA). OA binds to MbCO but does not bind to deoxy Mb. OA binding to Mb, however, does not alter its O affinity. Without any Mb, muscle has a significantly lower level of triglyceride (TG). In Mb knock-out (MbKO) mice, both heart and skeletal muscles have lower level of TG relative to the control mice. Training further decreases the relative TG in the MbKO skeletal muscle. Nevertheless, the absence of Mb and lower TG level in muscle does not impair the MbKO mouse performance as evidenced by voluntary wheel running measurements. The results support the hypothesis of a complex physiological role for Mb, especially with respect to fatty acid metabolism.

Myoglobin (Mb) is an oxygen binding protein found in vertebrate skeletal muscle, where it facilitates intracellular transport and storage of oxygen. This protein has evolved to suit unique physiological needs in the muscle of diving vertebrates that express Mb at much greater concentrations than their terrestrial counterparts. In this study, we characterized Mb oxygen affinity (P 50 ) from 25 species of aquatic and terrestrial birds and mammals. Among diving species, we tested for correlations between Mb P 50 and routine dive duration. Across all species examined, Mb P 50 ranged from 2.40 to 4.85 mmHg. The mean P 50 of Mb from terrestrial ungulates was 3.72±0.15 mmHg (range 3.70-3.74 mmHg). The P 50 of cetaceans was similar to terrestrial ungulates ranging from 3.54 to 3.82 mmHg, with the exception of the melonheaded whale, which had a significantly higher P 50 of 4.85 mmHg. Among pinnipeds, the P 50 ranged from 3.23 to 3.81 mmHg and showed a trend for higher oxygen affinity in species with longer dive durations. Among diving birds, the P 50 ranged from 2.40 to 3.36 mmHg and also showed a trend of higher affinities in species with longer dive durations. In pinnipeds and birds, low Mb P 50 was associated with species whose muscles are metabolically active under hypoxic conditions associated with aerobic dives. Given the broad range of potential globin oxygen affinities, Mb P 50 from diverse vertebrate species appears constrained within a relatively narrow range. High Mb oxygen affinity within this range may be adaptive for some vertebrates that make prolonged dives.

Subcutaneous adipose tissue (scAT) and peripheral blood mononuclear cells (PBMCs) play a significant role in obesity-associated systemic low-grade inflammation. High-fat diet (HFD) is known to induce inflammatory changes in both scAT and PBMCs. However, the time course of the effect of HFD on these systems is still unknown. The aim of the current study was to determine the time course of the effect of high fat diet (HFD) on PBMCs and scAT. New Zealand white rabbits were fed HFD for 5 or 10 weeks (i.e., HFD-5 and HFD-10), or regular chow (i.e., CNT-5 and CNT-10). Thereafter, metabolic and inflammatory parameters of PBMCs and scAT were quantitated. HFD induced hyperfattyacidemia in HFD-5 and HFD-10 groups, with the development of insulin resistance (IR) in HFD-10, while no changes were observed in scAT lipid metabolism and inflammatory status. HFD activated the inflammatory pathways in PBMCs of HFD-5 group, and induced modified autophagy in that of HFD-10. The rate of fat oxidation in PBMCs was directly associated with the expression of inflammatory markers; and tended to inversely associate with autophagosome formation markers in PBMCs. HFD affected systemic substrate metabolism, and the metabolic, inflammatory, and autophagy pathways in PBMCs in the absence of metabolic and inflammatory changes in scAT. Dietary approaches or interventions to avert HFD-induced changes in PBMCs could be essential in prevention of metabolic and inflammatory complications of obesity, and promote healthier living.

Northern elephant seals (NES, Mirounga angustirostris ) undergo an annual molt during which they spend ∼40 days fasting on land with reduced activity and lose approximately one-quarter of their body mass. Reduced activity and muscle load in stereotypic terrestrial mammalian models results in decreased muscle mass and capacity for force production and aerobic metabolism. However, the majority of lost mass in fasting female NES is from fat while muscle mass is largely preserved. Although muscle mass is preserved, potential changes to the metabolic and contractile capacity are unknown. To assess potential changes in NES skeletal muscle during molt, we collected muscle biopsies from 6 adult female NES before the molt and after ∼30 days at the end of the molt. Skeletal muscle was assessed for respiratory capacity using high resolution respirometry, and RNA was extracted to assess changes in gene expression. Despite a month of reduced activity, fasting, and weight loss, skeletal muscle respiratory capacity was preserved with no change in OXPHOS respiratory capacity. Molt was associated with 162 upregulated genes including those favoring lipid metabolism. We identified 172 downregulated genes including those coding for ribosomal proteins and genes associated with skeletal muscle force transduction and glucose metabolism. Following ∼30 days of molt, NES skeletal muscle metabolic capacity is preserved although mechanotransduction may be compromised. In the absence of exercise stimulus, fasting-induced shifts in muscle metabolism may stimulate pathways associated with preserving the mass and metabolic capacity of slow oxidative muscle.

increased the ADL by 30% (18·min to 24·min). Under postprandial conditions at a routine level of muscular exertion, doubling the Mb concentration did not increase the ADL (12·min). The convective oxygen transport needed to meet the metabolic demands (Heat Increment of Feeding, HIF) of the splanchnic organs during digestion and assimilation required a cardiac output that was not optimal for the efficient use of muscle oxygen stores. This resulted in an over perfusion of the muscles and incomplete use of myoglobin-bound oxygen. As a result, the postprandial ADL was limited by the amount of oxygen stored in the blood, and increasing the Mb concentration had no effect on the ADL. We hypothesize that myoglobin concentration is optimized for the type and duration of dives routinely made by Weddell seals, and that a further increase may not increase the ADL for most free-ranging dives.