Undulatory locomotion, as seen in the nematode Caenorhabditis elegans, is a common swimming gait of organisms in the low Reynolds number regime, where viscous forces are dominant. Although the nematode's motility is expected to be a strong function of its material properties, measurements remain scarce. Here, the swimming behavior of C. elegans is investigated in experiments and in a simple model. Experiments reveal that nematodes swim in a periodic fashion and generate traveling waves that decay from head to tail. The model is able to capture the experiments' main features and is used to estimate the nematode's Young's modulus E and tissue viscosity eta. For wild-type C. elegans, we find E approximately 3.77 kPa and eta approximately -860 Pa.s; values of eta for live C. elegans are negative because the tissue is generating rather than dissipating energy. Results show that material properties are sensitive to changes in muscle functional properties, and are useful quantitative tools with which to more accurately describe new and existing muscle mutants.

Disruption of neuronal Ca2ϩ homeostasis contributes to neurodegenerative diseases through mechanisms that are not fully understood. A polymorphism in CALHM1, a recently described ion channel that regulates intracellular Ca 2ϩ levels, is a possible risk factor for late-onset Alzheimer's disease. Since there are six potentially redundant CALHM family members in humans, the physiological and pathophysiological consequences of CALHM1 function in vivo remain unclear. The nematode Caenorhabditis elegans expresses a single CALHM1 homolog, CLHM-1. Here we find that CLHM-1 is expressed at the plasma membrane of sensory neurons and muscles. Like human CALHM1, C. elegans CLHM-1 is a Ca 2ϩ -permeable ion channel regulated by voltage and extracellular Ca 2ϩ. Loss of clhm-1 in the body-wall muscles disrupts locomotory kinematics and biomechanics, demonstrating that CLHM-1 has a physiologically significant role in vivo. The motility defects observed in clhm-1 mutant animals can be rescued by muscle-specific expression of either C. elegans CLHM-1 or human CALHM1, suggesting that the function of these proteins is conserved in vivo. Overexpression of either C. elegans CLHM-1 or human CALHM1 in neurons is toxic, causing degeneration through a necrotic-like mechanism that is partially Ca 2ϩ dependent. Our data show that CLHM-1 is a functionally conserved ion channel that plays an important but potentially toxic role in excitable cell function.

Caenorhabditis elegans locomotion is a stereotyped behavior that is ideal for genetic analysis. We integrated video microscopy, image analysis algorithms, and fluid mechanics principles to describe the C. elegans swim gait. Quantification of body shapes and external hydrodynamics and model-based estimates of biomechanics reveal that mutants affecting similar biological processes exhibit related patterns of biomechanical differences. Therefore, biomechanical profiling could be useful for predicting the function of previously unstudied motility genes.

is the widely expressed primary binding partner for IL-15. Because of the wide distribution in nonlymphoid tissues like skeletal muscle, adipose, or liver, IL-15/IL-15R␣ take part in physiological and metabolic processes not directly related to immunity. In fast muscle, lack of IL-15R␣ promotes an oxidative switch, with increased mitochondrial biogenesis and fatigue resistance. These effects are predicted to reproduce some of the benefits of exercise and, therefore, improve energy homeostasis. However, the direct effects of IL-15R␣ on metabolism and obesity are currently unknown. We report that mice lacking IL-15R␣ (IL-15R␣ Ϫ/Ϫ ) are resistant to diet-induced obesity (DIO). High-fat diet-fed IL-15R␣ Ϫ/Ϫ mice have less body and liver fat accumulation than controls. The leaner phenotype is associated with increased energy expenditure and enhanced fatty acid oxidation by muscle mitochondria. Despite being protected against DIO, IL-15R␣ Ϫ/Ϫ are hyperglycemic and insulin-resistant. These findings identify novel roles for IL-15R␣ in metabolism and obesity.interleukin-15 receptor alpha; diet-induced obesity; muscle; fatty acid oxidation; fatigue recovery; glucose homeostasis ACCUMULATION OF EXCESSIVE body fat is a physiological consequence of unnecessary caloric intake. With greater worldwide food production, often the caloric intake largely exceeds the physiological energy requirements, and as a result, the obesity pandemic is growing at alarming rates in both developed and developing countries (21,47). Apart from the role of environmental factors, particularly an energy-dense diet and sedentary lifestyle, obesity also has important genetic determinants that have been conserved across species. Identifying the molecular mechanisms regulating metabolic efficiency (the capacity to convert energy intake into storable energy forms) is of great interest because of the low success in using caloric restriction as a means to manage obesity. Indeed, a number of pathways have been recently identified that reduce the extent of dietinduced obesity (DIO) by decreasing metabolic efficiency rather than energy input (8,10,11,43,56,59,60). Targeting these pathways with pharmacological approaches may also have the advantage of reproducing some of the benefits normally associated with physical exercise. Together with caloric restriction, exercise is a mainstay of a healthy life style and contributes to the control of metabolic efficiency. In addition to converting energy into movement, exercise increases the rates of lipolysis and fat oxidation, promotes heat dissipation (49, 53), and causes long-term changes in the expression of numerous genes, including IL-15R␣/IL-15 (55).IL-15 and its primary binding partner IL-15R␣ have emerged as important regulators of cell functions in both lymphoid and nonlymphoid tissues. Their transcripts are detectable in a variety of tissues, including skeletal muscle, liver, or adipose (http://biogps.org/#gotoϭwelcome). Some of the proposed noncanonical roles of IL-15/IL-15R␣ signaling are mediating anabolic...

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Brain iron accumulates in several neurodegenerative diseases and can cause oxidative damage, but mechanisms of brain iron homeostasis are incompletely understood. Patients with mutations in the cellular iron-exporting ferroxidase ceruloplasmin (Cp) have brain iron accumulation causing neurodegeneration. Here, we assessed the brains of mice with combined mutation of Cp and its homolog hephaestin. Compared to single mutants, brain iron accumulation was accelerated in double mutants in the cerebellum, substantia nigra, and hippocampus. Iron accumulated within glia, while neurons were iron deficient. There was loss of both neurons and glia. Mice developed ataxia and tremor, and most died by 9 months. Treatment with the oral iron chelator deferiprone diminished brain iron levels, protected against neuron loss, and extended lifespan. Ferroxidases play important, partially overlapping roles in brain iron homeostasis by facilitating iron export from glia, making iron available to neurons.

Organophosphorus (OP) pesticide poisoning is a leading cause of morbidity and mortality in the developing world, affecting an estimated three million people annually. Much of the morbidity is directly related to muscle weakness, which develops 1-4 days after poisoning. This muscle weakness, termed the intermediate syndrome (IMS), leads to respiratory, bulbar, and proximal limb weakness and frequently necessitates the use of mechanical ventilation. While not entirely understood, the IMS is most likely due to persistently elevated acetylcholine (ACh), which activates nicotinic ACh receptors at the neuromuscular junction (NMJ). Thus, the NMJ is potentially a target-rich area for the development of new therapies for acute OP poisoning. In this manuscript, we discuss what is known about the IMS and studies investigating the use of nicotinic ACh receptor antagonists to prevent or mitigate NMJ dysfunction after acute OP poisoning.

Mutations in the human dysferlin gene cause Limb Girdle Muscular Dystrophy 2B (LGMD2B). The Caenorhabditis elegans dysferlin homolog, fer-1, affects sperms development but is not known to be expressed in or have a functional roles outside of the male germline. Using several approaches, we show that fer-1 mRNA is present in C. elegans muscle cells but is absent from neurons. In mammals, loss of muscle-expressed dysferlin causes transcriptional deregulation of muscle expressed genes. To determine if similar alterations in gene expression are initiated in C. elegans due to loss of muscle-expressed fer-1, we performed whole genome Affymetrix microarray analysis of two loss-of-function fer-1 mutants. Both mutants gave rise to highly similar changes in gene expression and altered the expression of 337 genes. Using multiple analysis methods, we show that this gene set is enriched for genes known to regulate the structure and function of muscle. However, these transcriptional changes do not appear to be in response to gross sarcomeric damage, since genetically sensitized fer-1 mutants exhibit normal thin filament organization. Our data suggest that processes other than sarcomere stability may be affected by loss of fer-1 in C. elegans muscle. Therefore, C. elegans may be an attractive model system in which to explore new muscle-specific functions of the dysferlin protein and gain insights into the molecular pathogenesis of LGMD2B.