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Chronic inflammatory diseases such as heart failure, cancer and arthritis have secondary effects on skeletal muscle that cause weakness and exercise intolerance. These symptoms exacerbate illness and make death more likely. Weakness is not simply a matter of muscle atrophy. Functional studies show that contractile dysfunction, i.e. a reduction in specific force, makes an equally important contribution to overall weakness. The most clearly defined mediator of contractile dysfunction is tumour necrosis factor (TNF). TNF serum levels are elevated in chronic disease, correlate with muscle weakness, and are a predictor of morbidity and mortality. Research is beginning to unravel the mechanism by which TNF depresses specific force. TNF acts via the TNFR1 receptor subtype to depress force by increasing cytosolic oxidant activity. Oxidants depress myofibrillar function, decreasing specific force without altering calcium regulation or other aspects of myofibrillar mechanics. Beyond these concepts, the intracellular mechanisms that depress specific force remain undefined. We do not know the pathway by which receptor-ligand interaction stimulates oxidant production. Nor do we know the type(s) of oxidants stimulated by TNF, their intracellular source(s), or their molecular targets. Investigators in the field are pursuing these issues with the long-term goal of preserving muscle function in individuals afflicted by chronic disease.

Doxorubicin is a chemotherapeutic agent prescribed for a variety of tumors. While undergoing treatment, patients exhibit frequent symptoms that suggest respiratory muscle weakness. Cancer patients can receive doxorubicin chemotherapy through either intravenous (IV) or intraperitoneal (IP) injections. We hypothesized that respiratory muscle function would be depressed in a murine model of chemotherapy. We tested this hypothesis by treating C57BL/6 mice with a clinical dose of doxorubicin (20 mg/kg) via IV or IP injection. Three days later we measured contractile properties of muscle fiber bundles isolated from the diaphragm. Doxorubicin consistently depressed diaphragm force with both methods of administration (P < 0.01). Doxorubicin IP exaggerated the depression in diaphragm force and stimulated tissue inflammation and muscle fiber injury. These results suggest that clinically relevant doses of doxorubicin cause respiratory muscle weakness and that the loss of function depends, in part, on the route of administration.

Alternatives to the canonical insulin-stimulated pathway for glucose uptake are exercise- and exogenous reactive oxygen species (ROS)-stimulated glucose uptake. We proposed a model wherein mechanical loading, i.e. stretch, stimulates production of ROS to activate AMP-activated kinase (AMPK) to increase glucose uptake. Immunoblotting was used to measure protein phosphorylation; the fluorochrome probe 2′7′-dichlorofluorescin diacetate was used to measure cytosolic oxidant activity and 2-deoxy-d[1,2-3H]glucose was used to measure glucose uptake. The current studies demonstrate that stretch increases ROS, AMPKα phosphorylation and glucose transport in murine extensor digitorum longus (EDL) muscle (+121%, +164% and +184%, respectively; P 0.16). We also demonstrate that stretch-stimulated glucose uptake persists in the presence of the phosphatidylinositol 3-kinase (PI3-K) inhibitors wortmannin and LY294001 (P 0.99). These data indicate that stretch-stimulated glucose uptake in skeletal muscle is mediated by a ROS- and p38 MAPK-dependent mechanism that appears to be AMPKα2- and PI3-K-independent.

Underlying the pathogenesis of chronic disease is the state of oxidative stress. Oxidative stress is an imbalance in oxidant and antioxidant levels. If an overproduction of oxidants overwhelms the antioxidant defenses, oxidative damage of cells, tissues, and organs ensues. In some cases, oxidative stress is assigned a causal role in disease pathogenesis, whereas in others the link is less certain. Along with underlying oxidative stress, chronic disease is often accompanied by muscle wasting. It has been hypothesized that catabolic programs leading to muscle wasting are mediated by oxidative stress. In cases where disease is localized to the muscle, this concept is easy to appreciate. Transmission of oxidative stress from diseased remote organs to skeletal muscle is thought to be mediated by humoral factors such as inflammatory cytokines. This review examines the relationship between oxidative stress, chronic disease, and muscle wasting, and the mechanisms by which oxidative stress acts as a catabolic signal.

Atrogin1/MAFbx is an ubiquitin ligase that mediates muscle atrophy in a variety of catabolic states. We recently found that H2O2 stimulates atrogin1/MAFbx gene expression. Since the cytokine tumor necrosis factor-alpha (TNF-alpha) stimulates both reactive oxygen production and general activity of the ubiquitin conjugating pathway, we hypothesized that TNF-alpha would also increase atrogin1/MAFbx gene expression. As with H2O2, we found that TNF-alpha exposure up-regulates atrogin1/MAFbx mRNA within 2 h in C2C12 myotubes. Intraperitoneal injection of TNF-alpha increased atrogin1/MAFbx mRNA in skeletal muscle of adult mice within 4 h. Exposing myotubes to either TNF-alpha or H2O2 also produced general activation of the mitogen-activated protein kinases (MAPKs): p38, ERK1/2, and JNK. The increase in atrogin1/MAFbx gene expression induced by TNF-alpha was not altered significantly by ERK inhibitor PD98059 or the JNK inhibitor SP600125. In contrast, atrogin1/MAFbx up-regulation and the associated increase in ubiquitin conjugating activity were both blunted by p38 inhibitors, either SB203580 or curcumin. These data suggest that TNF-alpha acts via p38 to increase atrogin1/MAFbx gene expression in skeletal muscle.

Cancer cachexia is a severe skeletal muscle wasting syndrome directly responsible for 30% of all cancer deaths. Cancer exerts paracrine effects on skeletal muscle that trigger myosin loss and metabolic dysfunction. Clinical trials using cyclooxygenase 2 (COX2) inhibitors to treat cachexia had some success. Therefore, we hypothesized that tumor-induced COX2 expression contributes to myosin loss and mitochondrial dysfunction. We incubated C2C12 myotubes with control or Lewis lung carcinoma conditioned medium (LLCCM) for 48hr. We measured protein content by western blot, and oxygen consumption rate (OCR) of intact myotubes using a Seahorse XF24. Protein content is presented as means±SD in arbitrary units (n=6/group, t test). OCR is presented in pmoles O2/min (n=8/group, repeated measures ANOVA). LLCCM treatment decreased myosin content by 70%, from 7.2±2.7 to 2.1±1 AU (p

Summary The case notes of 126 of the 134 children undergoing craniofacial operations in the Hospitals for Sick Children, in the years 1986 to 1990 inclusive, were studied. The ages ranged between one month and 12 years, with 50% of cases being in the first year of life. Anaesthesia was conducted in accordance with standard neurosurgical techniques. Induced hypotension was not employed. The major problems encountered were haemorrhage (20% required transfusion in excess of the estimated blood volume) and bradycardia associated with orbital manipulation (12%). Four patients had major intraoperative complications requiring resuscitation. Thirty-seven children required postoperative pulmonary ventilation, but the incidence decreased markedly during the series (64% in 1986 to 6.5% in 1989). There were no deaths or cases of permanent neurological impairment.

Exogenous ROS stimulate insulin-independent glucose uptake by skeletal muscle. AMP-activated protein kinase (AMPK) is a mediator of insulin-independent glucose transport. This study tested the hypo...

Butorphanol, 1, 2, and 4 mg/70 kg, and meperidine, 40 and 80 mg/70 kg, were compared for analgesic activity and side effects in 104 hospitalized postoperative patients. Butorphanol proved to be 30 to 40 times as potent as meperidine on a weight basis. Both medications provided maximum pain relief approximately 1 hr after administration. The most common side effect in all groups was drowsiness.