Dietary restriction (DR) is a metabolic intervention that extends the lifespan of multiple species, including yeast, flies, nematodes, rodents, and, arguably, rhesus monkeys and humans. Hallmarks of lifelong DR are reductions in body size, fecundity, and fat accumulation, as well as slower development. We have identified atx-2, the Caenorhabditis elegans homolog of the human ATXN2L and ATXN2 genes, as the regulator of these multiple DR phenotypes. Down-regulation of atx-2 increases the body size, cell size, and fat content of dietary-restricted animals and speeds animal development, whereas overexpression of atx-2 is sufficient to reduce the body size and brood size of wild-type animals. atx-2 regulates the mechanistic target of rapamycin (mTOR) pathway, downstream of AMP-activated protein kinase (AMPK) and upstream of ribosomal protein S6 kinase and mTOR complex 1 (TORC1), by its direct association with Rab GDP dissociation inhibitor β, which likely regulates RHEB shuttling between GDP-bound and GTP-bound forms. Taken together, this work identifies a previously unknown mechanism regulating multiple aspects of DR, as well as unknown regulators of the mTOR pathway. They also extend our understanding of diet-dependent growth retardation, and offers a potential mechanism to treat obesity.Caenorhabditis elegans | metabolism | mTOR pathway | TORC1 D ietary restriction (DR), limiting food consumption below ad libitum to levels that do not cause malnutrition, is a highly conserved metabolic intervention. Different DR regimes extend the lifespan of most tested animal species (1). Moreover, DR regimens have been found to reduce the risk of diabetes in monkeys and to positively change metabolic health biomarkers in humans (2). Lifelong DR causes reduced body size, lower fat levels, and a smaller brood size (3-6). Although the pathways by which DR extends lifespan have been thoroughly investigated, less is known about the causes of reduced body size and fat content.Multiple DR regimens have been developed for Caenorhabditis elegans (7). Surprisingly, the different DR regimens vary in the genes essential for lifespan extension (7). For example, DR can be achieved by diluting the bacteria in a liquid medium. This intervention, which extends the lifespan and decreases animal size, is partially dependent on both daf-16, a key transcription factor of the insulin-like signaling pathway, and aak-2, the catalytic subunit of AMP-activated protein kinase (AMPK) (7,8). In a different DR model, a mutation in the eat-2 gene decreases the rate of pharyngeal contractions, limiting the animals' feeding rate. Unlike bacterial dilution, this model was shown to be independent of both daf-16 and aak-2, at least with respect to lifespan (7).The mechanistic target of rapamycin (mTOR) pathway is a key regulator of multiple processes, including transcription and translation, protein and lipid synthesis, cell growth and size, and cellular metabolism (9). It contains two main protein complexes, mTOR complex 1 (TORC1) and complex 2 (TORC2) (10). TOR...

There are numerous heritable diseases associated with mutations in the LMNA gene. Most of these laminopathic diseases, including several muscular dystrophies, are autosomal dominant and have tissue-specific phenotypes. Our previous studies have shown that the globally expressed EmeryDreifuss muscular dystrophy (EDMD)-linked lamin mutation, L535P, disrupts nuclear mechanical response specifically in muscle nuclei of C. elegans leading to atrophy of the body muscle cells and to reduced motility. Here we used RNA sequencing to analyze the global changes in gene expression caused by the L535P EDMD lamin mutation in order to gain better understanding of disease mechanisms and the correlation between transcription and phenotype. Our results show changes in key genes and biological pathways that can help explain the muscle specific phenotypes. In addition, the differential gene expression between wild-type and L535P mutant animals suggests that the pharynx function in the L535P mutant animals is affected by this lamin mutation. Moreover, these transcriptional changes were then correlated with reduced pharynx activity and abnormal pharynx muscle structure. Understanding disease mechanisms will potentially lead to new therapeutic approaches toward curing EDMD.

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1. Embryos of Rana temporaria have been dissected and shape alterations of different parts of the embryo, taking place within 1 h of separation, have been studied. Two categories of deformation have been revealed. 2. The first category comprises those deformations which take place immediately after separation. They are insensitive to cooling, cyanide and Cytochalasin B treatment. These deformations, which consist of a shortening of initially elongated cells, are considered to be the passive relaxations of previously established elastic tensile stresses. 3. Deformations of the second category proceed more slowly. They are inhibited by cooling, cyanide and Cytochalasin B treatment, are accompanied by elongation and migration of cells and occasionally lead to rather complex morphodifferentiations of isolated fragments. These processes are considered to be the result of the active work of intracellular contractile systems, either pre-existing or induced de novo. 4. By analysing the arrangement of the passive deformations we have constructed maps of mechanical stresses in embryos from late blastula up to the early tail-bud stage. At several embryonic stages drastic transformations of the stress pattern occur, these transformations being separated by periods during which the pattern of stress distribution remains topologically constant. 5. A correlation between the arrangement of stress lines and the presumptive morphological pattern of the embryo is pointed out. 6. Some possible relations between tensile tissue stresses and active mechanochemical processes are discussed.