Cancer cachexia is a wasting syndrome causing involuntary weight loss and muscle atrophy. PARP1 is a nicotinamide dinucleotide-dependent enzyme that modifies target proteins by PARylation. The reversal process, dePARylation, is mediated by the PARG enzyme. PARP1 inhibitors are potent cancer agents, while PARG inhibitors are in clinical trials for similar cancers. Here we examine the role of PARylation on muscle homeostasis in cancer cachexia. We employed mouse models with inducible muscle specific knockouts of Parp1 (Parp1-IMKO) or Parg (Parg-IMKO) to investigate their implications on skeletal muscle in a cancer cachexia model. We assessed muscle loss, grip strength, and gene expression. Results show that Parp1- IMKO mice had increased muscle wasting, while Parg-IMKO had degradation rates similar to wild-type mice during cancer cachexia. This suggests reduced PARylation might worsen cancer cachexia, while an increase does not. This supports PARG inhibitor development as anticancer alternatives. Our study highlights challenges with PARP1 inhibitors and the need to study PARylation and dePARylation in muscle health during cancer cachexia, impacting clinical strategies using PARP1 or PARG inhibitors.

No description available.

No description available.

Base teórica: A osteoartrite é uma doença crônica cuja principal característica é a degradação progressiva da cartilagem articular. Além do acometimento articular, frequentemente, os pacientes com osteoartrite apresentam fraqueza e atrofia dos músculos periarticulares. Apesar disso, os mecanismos moleculares envolvidos na perda muscular relacionada à osteoartrite não são conhecidos. Os principais mecanismos já estudados, em outras condições, estão relacionados ao aumento da degradação e à redução da síntese de proteínas musculares e a déficits na ativação das células-satélite, responsáveis pela regeneração muscular. A miostatina, um importante regulador negativo do crescimento da massa muscular, estimula o aumento da degradação e a redução da síntese de proteínas musculares. Por outro lado, MyoD e miogenina, são marcadores de proliferação e de diferenciação de células-satélite, respectivamente. Objetivos: Investigar os mecanismos moleculares envolvidos na perda muscular em um modelo animal de osteoartrite induzida por transecção do ligamento cruzado anterior em ratas. Métodos: Ratas Wistar fêmeas foram alocadas em dois grupos: OA (submetidas à cirurgia de transecção do ligamento cruzado anterior do joelho direito) e SHAM (submetidas à cirurgia fictícia do joelho direito). Durante o período experimental de 12 semanas foram avaliados, semanalmente, o peso corporal e a locomoção exploratória espontânea. Após a eutanásia, foram coletadas as articulações do joelho direito para confirmação do desenvolvimento da doença. Os músculos gastrocnêmio, tibial-anterior e sóleo, da pata posterior direita, foram dissecados, pesados e congelados. O músculo gastrocnêmio foi utilizado para a avaliação da atrofia muscular, através da análise da área seccional da miofibra, e para análise da expressão proteica de miostatina, MyoD e miogenina. Resultados: A locomoção exploratória espontânea, o peso corporal e o peso dos músculos gastrocnêmio, tibial-anterior e sóleo não apresentaram diferença significativa entre os grupos OA e SHAM. A histopatologia da articulação do joelho confirmou o desenvolvimento da doença nos animais do grupo OA. A área do músculo gastrocnêmio demonstrou redução de aproximadamente 10% no grupo OA, em comparação com o grupo SHAM. O grupo OA apresentou aumento na expressão proteica de miostatina e redução na expressão proteica de miogenina. A expressão proteica de MyoD não apresentou diferença entre os grupos. Conclusão: A atrofia do músculo gastrocnêmio presente na osteoartrite induzida por transecção do ligamento cruzado anterior envolve aumento na expressão de miostatina e redução na expressão de miogenina. Nesse modelo, a perda muscular pode estar relacionada à proteólise induzida pelos níveis aumentados de miostatina e ao déficit na diferenciação das células-satélite devido à redução na expressão de miogenina. / Background: Osteoarthritis is a chronic joint disease primarily characterized by cartilage loss. In addition to joint impairment, patients with osteoarthritis often suffer from weakness and atrophy of the periarticular muscles. However, the molecular mechanisms involved in osteoarthritis-related muscle wasting are not known. The main mechanisms studied, in other conditions, are related to increased degradation and reduced synthesis of muscle protein and to deficits in the activation of satellitecells, which are responsible for muscle regeneration. Myostatin, an important negative regulator of muscle growth, stimulates the increase of degradation and the reduction of synthesis of muscle protein. Moreover, MyoD and myogenin are markers of proliferation and differentiation of satellite-cells, respectively. Objective: To investigate the pathways involved in muscle wasting in a model of osteoarthritis induced by anterior cruciate ligament transection (ACL) in rats. Methods: Female Wistar rats were allocated into two groups: OA (submitted to the ACL transection) and SHAM (submitted to surgical procedures without ACL transection). The spontaneous exploratory locomotion and the body weight of animals were evaluated weekly. In the twelfth week after the induction of disease, animals were euthanized and the right knee joints were collected for further confirmation of the disease by histopathology. Gastrocnemius, tibialis-anterior and soleus muscles from right hind paw were dissected, weighed and frozen. Gastrocnemius was used for evaluation of muscle atrophy, by cross-sectional area measurement, and protein expression of myostatin, MyoD and myogenin. Results: Spontaneous exploratory locomotion, body weight and weight of muscles showed no difference between OA and SHAM groups. The histopathology of the knee joints confirmed the development of the disease in animals from OA group. Gastrocnemius area of animals from OA group had a reduction of about 10% compared to animals from SHAM group. Protein expression of myostatin was increased in animals from OA group, while myogenin expression was decreased. MyoD expression was similar in both OA and SHAM groups. Conclusion: Gastrocnemius atrophy in osteoarthritis induced by ACL transection involves increased protein expression of myostatin and decreased protein expression of myogenin. In this model, muscle wasting may be linked to myostatininduced proteolysis and to deficits in satellite-cell differentiation due to decreased expression of myogenin.

Early-lactating dairy cows mobilize body protein, primarily from skeletal muscle, to provide amino acids which are directed towards gluconeogenesis and milk protein synthesis. Propylene glycol (PG) is a precursor of ruminal propionate, and our hypothesis was that its dietary inclusion could attenuate skeletal muscle wasting by reducing amino acid-driven gluconeogenesis. The major objectives of this study were to delineate the effects of pre- and post-partum PG supplementation in transition dairy cows on whole-body nitrogen (N) balance, urinary 3-methylhistidine (3-MH) excretion, body composition, and gene expression profiles for the major protein degradation pathways in skeletal muscle. Sixteen pregnant cows (7 primiparous and 9 multiparous) were paired based on expected calving dates and then randomly assigned within each pair to either a basal diet (control) or basal diet plus 600 mL/d of PG (PG). Diets were fed twice daily for ad libitum intake, and PG was fed in equal amounts as a top dress. All measurements were conducted at 3 time intervals starting at d -14 ± 5, d 15 and d 38 relative to calving. Propylene glycol had no effect (P > 0.05) on whole-body N balance, urinary 3-MH excretion, and body composition. However, N balance was lower (P < 0.001) at d 15 and d 38, compared to d -14. Urinary excretion of 3-MH was lower at d -14 than at d 15 (P = 0.01) and d 38 (P = 0.001). Supplemental PG had no effect (P > 0.05) on body weight (BW), and all components of empty BW. On average, cows fed both diets mobilized 19 kg of body fat and 14 kg of body protein between d -14 and d 38. Supplemental PG had no effect on mRNA abundance in skeletal muscle for m-calpain (P = 0.96) and 14-kDa ubiquitin-carrier protein E2 (14-kDa E2) (P = 0.54); however, PG supplementation down-regulated mRNA expression for µ-calpain at d 15 (P = 0.02), and tended to down-regulate mRNA expression for ubiquitin at d 15 (P = 0.07) and proteasome 26S subunit-ATPase at d 38 (P = 0.097). Relative to calving, mRNA abundance for m-calpain (P = 0.02) and µ-calpain (P = 0.005) were higher at d 15 compared to d -14 and d 38. Messenger RNA abundance for ubiquitin (P = 0.07) and 14-kDa E2 (P = 0.005) were lower at d 38 compared to d 15. In summary, these results demonstrate that up-regulation of the Ca2+-dependent and ubiquitin-mediated proteolytic pathways are the mechanisms by which skeletal muscle wasting occurs in early-lactating cows. In addition, dietary supplementation with PG may down-regulate some of these proteolytic pathways, thereby potentially attenuating undesirable skeletal muscle wasting.

Early-lactating dairy cows mobilize body protein, primarily from skeletal muscle, to provide amino acids which are directed towards gluconeogenesis and milk protein synthesis. Propylene glycol (PG) is a precursor of ruminal propionate, and our hypothesis was that its dietary inclusion could attenuate skeletal muscle wasting by reducing amino acid-driven gluconeogenesis. The major objectives of this study were to delineate the effects of pre- and post-partum PG supplementation in transition dairy cows on whole-body nitrogen (N) balance, urinary 3-methylhistidine (3-MH) excretion, body composition, and gene expression profiles for the major protein degradation pathways in skeletal muscle. Sixteen pregnant cows (7 primiparous and 9 multiparous) were paired based on expected calving dates and then randomly assigned within each pair to either a basal diet (control) or basal diet plus 600 mL/d of PG (PG). Diets were fed twice daily for ad libitum intake, and PG was fed in equal amounts as a top dress. All measurements were conducted at 3 time intervals starting at d -14 ± 5, d 15 and d 38 relative to calving. Propylene glycol had no effect (P > 0.05) on whole-body N balance, urinary 3-MH excretion, and body composition. However, N balance was lower (P < 0.001) at d 15 and d 38, compared to d -14. Urinary excretion of 3-MH was lower at d -14 than at d 15 (P = 0.01) and d 38 (P = 0.001). Supplemental PG had no effect (P > 0.05) on body weight (BW), and all components of empty BW. On average, cows fed both diets mobilized 19 kg of body fat and 14 kg of body protein between d -14 and d 38. Supplemental PG had no effect on mRNA abundance in skeletal muscle for m-calpain (P = 0.96) and 14-kDa ubiquitin-carrier protein E2 (14-kDa E2) (P = 0.54); however, PG supplementation down-regulated mRNA expression for µ-calpain at d 15 (P = 0.02), and tended to down-regulate mRNA expression for ubiquitin at d 15 (P = 0.07) and proteasome 26S subunit-ATPase at d 38 (P = 0.097). Relative to calving, mRNA abundance for m-calpain (P = 0.02) and µ-calpain (P = 0.005) were higher at d 15 compared to d -14 and d 38. Messenger RNA abundance for ubiquitin (P = 0.07) and 14-kDa E2 (P = 0.005) were lower at d 38 compared to d 15. In summary, these results demonstrate that up-regulation of the Ca2+-dependent and ubiquitin-mediated proteolytic pathways are the mechanisms by which skeletal muscle wasting occurs in early-lactating cows. In addition, dietary supplementation with PG may down-regulate some of these proteolytic pathways, thereby potentially attenuating undesirable skeletal muscle wasting.

Inadequate nutrition in preschool-aged children in an urban indigenous community outside of Santo Domingo, Ecuador has a negative impact on growth and development. Nutritional assessments have shown that children are underweight and that there are some effects of stunting and wasting in the population. This study was conducted to assess the extent of food security in this indigenous community in preparation for addressing two of the Millennium Development Goals for 2015: reducing the under-five child mortality rate by two-thirds and eradicating extreme poverty and hunger. An aim was to validate on-site assessment measures in this indigenous community regarding geographic circumstances, transportation, food culture systems and other barriers to food intake. These are interrelated and impact nutritional data collected on Tsáchila families in Ecuador. Mixed methods research were conducted to examine the factors that contribute to nutritional intake. The results showed observed food intake was less than food intake reported on the FFQ. Micronutrient and macronutrient levels, weight-for-height and height-for-age measures were below the WHO standard deviations for Z-scores for this population.

No description available.

Oceanic island volcanoes such as those in the Hawaiian, Canary and Galapagos Islands are known to become unstable, causing failures of the subaerial and submarine slopes of the volcanic edifices. These mass wasting events appear to be the primary source of destruction and loss of volume of many oceanic islands, but our knowledge of mass wasting is still rudimentary in many seamount and island chains. To better understand mass wasting in the western Galapagos Islands, multi-beam bathymetry and backscatter sidescan sonar images were used to examine topography and acoustic backscatter signatures that are characteristic of mass wasting. Observations show that mass wasting plays an important role in the development of Galapagos volcanoes. While volcanic activity continues to conceal the submarine terrain, the data show that four forms of mass wasting are identified including debris flows, slumps sheets, chaotic slumps, and detached blocks. A total of 23 mass wasting features were found to exist in the western Galapagos Islands, including fourteen debris flows with one that incorporated a set of detached blocks, seven slump sheets, and one chaotic slump. Some of the indentified features have obvious origination zones while the sources of others are not clearly identifiable. Approximately 73 percent of the surveyed coastlines are affected by slumping on the steep upper slopes and ~64 percent are affected by debris flows on the lower slopes. Unlike the giant landslides documented by GLORIA imagery around the Hawaiian Islands, the western Galapagos Islands appear to be characterized by small slump sheets existing along the steep shallow submarine flanks of the island and by debris flows that are flanked by rift zones and extend off the platform. This study indicates that submarine mass wasting is widespread in the western Galapagos, suggesting that the production of small-scale downslope movement is part of the erosive nature of these oceanic volcanic islands.

Thesis (M.S.)--University of Wisconsin--Stevens Point, 2008. / Submitted in partial fulfillment of the requirements of the degree Master of Science in Natural Resources (Wildlife), College of Natural Resources. Includes bibliographical references.