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跌倒和肌肉減少症是威脅老年人身體健康和生命安全的兩個重要問題。肌肉減少症所致的肌肉力量減弱和平衡能力下降是導致老年人跌倒的最主要原因。老年人跌倒最普遍和最嚴重的後果是脆性骨折。跌倒所致的脆性骨折是常見老年病，同時也是導致老年人生活品質下降和死亡的最主要原因之一。高頻低幅振動(LMHFV)是一種非侵入性生物物理干預手段，通過給予全身物理震動刺激，可有效提高肌肉功能和改善骨質。由此推測高頻低幅振動治療有望應用於預防跌倒/骨折及延緩肌肉減少。 / 本研究的目的在於，採用臨床隨機對照研究方法，通過對社區老年人進行高頻低幅振動治療，探索高頻低幅振動治療在預防跌倒/骨折、降低骨折發生率以及延緩肌肉量下降的作用。本研究假設高頻低幅振動治療可有效提高肌肉力量和改善骨質，從而降低骨折風險、跌倒率以及骨折發生率。本研究將分成兩部分進行以驗證此假說。 / 第一部分研究中，710名60歲或以上的社區老年人按社區中心為單位隨機分成振動治療組和對照組。振動治療組給予35Hz，0.3g的振動治療，並以每天20分鐘，每週5 天，持續18 個月；對照組則如常生活而不予振動治療。18個月治療過程中，振動治療組的跌倒率低於對照組46% (p=0.001)。同時，治療組的在平衡力測試中的反應時間、移動速度，和最遠移動距離也都有明顯改善 (所有指標 p<0.001）。在高頻低幅振動治療停止一年後，振動治療組的主導腿和非主導腿肌肉力量仍高於接受振動治療前 (p=0.029, p=0.002)。在平衡力測試中，治療組的反應時間、移動速度以及最遠移動距離也明顯優於對照組 (p=0.001，p=0.014，p=0.007)。在停止治療的一年期間，兩組受試者的肌肉力量，平衡能力以及生活品質均有下降的趨勢，但兩組的下降率並無明顯的差異。 / 第二部分的設計是基於第一部分的研究成果，目的在於更深入研究高頻低幅振動治療對肌肉功能、肌肉量以及肌肉質素的影響。60名社區老人隨機分成對照組和振動治療組。振動治療組給予35Hz，0.3g的高頻低幅振動治療，並以每天20分鐘，每週5天，持續9個月; 對照組則如常生活而不予振動治療。9個月後，治療組的主導腿和非主導腿的肌肉力量明顯高於對照組 (p<0.001，p=0.003)。在用以評估肌肉力量以及平衡力的計時起立坐下測試中，振動治療組用以完成連串起立及坐下動作的時間明顯低於對照組 (p=0.009)。振動治療組的下肢功能尺度問卷評估結果也明顯優於對照組 (p=0.002)。雖然兩組間的身體成份及肌電圖測試結果並無明顯差異，但治療組的肌肉量和肌電圖平均頻率均有上升的趨勢。而且，在兩部分實驗中，受試者對高頻低幅振動治療均有良好的耐受性，目前並沒有發現對受試者身體產生不利影響。因此，高頻低幅振動治療可安全地應用於社區老年人。 / 總括而言研究結果證明高頻低幅振動治療可明顯降低老年人跌倒發生率。9至18個月的振動治療可明顯改善老年人下肢功能和平衡力。在完成為期18個月高頻低幅振動治療後的1年，肌肉功能仍高於對照組，表明高頻低幅振動治療具有長期療效。因此，高頻低幅振動治療應在社區推廣作為老年人跌倒的預防方案之一。 / Fall and sarcopenia are two major problems among elderly. Poor muscle strength and balancing ability resulted from sarcopenia are the major causes of fall incidences. Fragility fracture is one of the most common and serious consequences of falls, which accounts for most of the deaths, as well as morbidity and poor quality of life. Low magnitude high frequency vibration (LMHFV) treatment is a non-invasive biophysical modality to provide a whole-body mechanical stimulation, which was previously shown to improve muscle performance and bone quality implying the potential application for fall/fracture prevention and reducing muscle loss. / The objectives of this study were to conduct prospective randomized controlled clinical trials to investigate the effect of LMHFV treatment on fall/fracture prevention, fracture risks and muscle loss among community elderly. It was hypothesized that LMHFV treatment could enhance muscle performance and bone quality, thus reducing the fracture risks, fall incidence and fracture rate. Two parts of studies were designed to testify the hypotheses. / In the Part I study, a total of 710 community elderly who were aged 60 years or above were recruited and randomized into vibration or control group on center-basis. The subjects in vibration group received LMHFV treatment (35Hz, 0.3g) 20min/day and 5days/week for 18 months, while control group remained sedentary. During the 18-month study period, the vibration group had reported 46% lower fall incidence rate when compared with control group (p=0.001). Significant improvements were found in reaction time, movement velocity and maximum excursion of balancing ability assessment, and also the quadriceps muscle strength (p<0.001 to all). After ceasing the LMHFV for 1 year, the muscle strength of dominant and non-dominant legs in vibration group were still significantly better than the baseline assessed before intervention (p=0.029 and 0.002 respectively), as compared with the control. In balancing ability test, the reaction time, movement velocity and maximum excursion of vibration group also remained significantly improved, as compared with the control group (p=0.001, 0.014 and 0.007 respectively). During the 1 year post-intervention period, both groups had shown a decreasing trend of muscle strength, balancing ability and quality of life but the rate of changes were not significantly different between two groups. / With reference to the results of Part I study, the Part II study was designed to investigate further the effects of LMHFV on muscle performance, mass and quality. 60 community elderly were recruited and randomized into either vibration or control group. Vibration group subjects received LMHFV treatment (35Hz, 0.3g) 20min/day, 5days/week for 9 months, while control group remained sedentary. Significant enhancement of dominant and non-dominant leg muscle strength was observed in the vibration group after 9 months LMHFV (p<0.001 and =0.003 respectively). In the chair rising test assessing muscle power and balancing ability, vibration group showed significantly shorter time needed for sit-to-stand cycles than the control (p=0.009). Significant increase of the lower extremity functional scale was also observed in the vibration group (p=0.002). No significant findings were found in the body composition and vibromyography (VMG) assessment, however, a trend of increasing lean mass and VMG mean frequency were observed. Also, minimal adverse effects were documented in both parts of study; all subjects were well-tolerated for LMHFV treatment. LMHFV is therefore safe and applicable to elderly in the community setting. / LMHFV was demonstrated to reduce fall incidences significantly. Significant effects on improving lower limbs function and balancing ability were observed as early as 9 months after treatment. Enhancement of muscle performance still remained significant 1 year after completion of 18-month LMHFV treatment, indicating strong residual effects of LMHFV. Use of LMHFV in the community as an effective fall prevention program is recommended. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Li, Chi Yu. / Thesis (Ph.D.) Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 154-167). / Abstracts also in Chinese.

Les sociétés économiquement développées sont confrontées à la problématique du vieillissement de leur population associée à la recrudescence des pathologies dégénératives. Parmi les manifestations du vieillissement, l'atteinte de l'appareil locomoteur (ostéoporose et sarcopénie) est considérée comme un problème majeur de santé publique. De ce fait, le développement de mesures préventives permettant de préserver la santé des séniors constitue un véritable enjeu de santé publique. La recherche scientifique fournit de nombreuses preuves concernant l'importance de l'alimentation dans la diminution ou l'exacerbation de certaines maladies. Ces observations confirment le vieux concept soutenant que l'adoption d'une alimentation équilibrée permet le maintien d'un état de santé satisfaisant, en particulier avec l'avancée en âge. A ce jour, le potentiel de l'huile d'olive, en tant que telle ou comme vecteur de nutriments lipophiles d'intérêt pour la prévention nutritionnelle de l'ostéoporose et de la sarcopénie, n'a jamais été testé. La prévalence de l'ostéoporose étant très supérieure chez la femme ménopausée qui souffre également d'une perte musculaire accélérée, cette population a été ciblée dans la présente étude. Dans une première étape, des résultats originaux ont été obtenus concernant l'effet de l'ovariectomie sur le métabolisme musculaire. Ainsi, notre travail montre qu'après ablation des ovaires, la synthèse protéique musculaire est réduite, en association avec une diminution d'un marqueur de la protéolyse de ce tissu. Pris dans son ensemble, ces résultats démontrent un ralentissement du renouvellement protéique musculaire suite à l'ovariectomie. En termes de mécanismes mis en jeu, une augmentation de l'infiltration lipidique tissulaire a été observée. En parallèle du ralentissement du renouvellement musculaire après ovariectomie, une augmentation du renouvellement osseux, classiquement décrit dans la littérature, a été mis en évidence. Dans un second temps, l'effet de l'huile d'olive et plus particulièrement des polyphénols présents dans cet aliment en association avec la vitamine D et l'acide ocosahexaénoïque et leur éventuelle synergie a été évalué à l'aide d'un modèle d'ostéoporose post-ménopausique. Des souris ovariectomisées ont été soumises à une des 4 huiles suivantes : huile de maïs, huile d'olive raffinée, huile d'olive extra vierge ou huile de poisson. Pour chaque huile, un groupe supplémentaire de souris ovariectomisées a reçu de l'huile enrichie en vitamine D. Cette étude a permis de mettre en évidence un effet protecteur de l'association de l'huile d'olive extra vierge et de la vitamine D sur la perte osseuse induite par l'ovariectomie chez la souris. En effet, l'accélération du renouvellement osseux consécutive à la carence estrogénique est freinée par cette association de nutriments, qui diminuent également l'expression des marqueurs du stress oxydant et de l'inflammation. Les résultats obtenus sont en cours de validation chez l'Homme grâce à une investigation clinique réalisée chez des femmes ménopausées. Celle-ci a été mise en place au cours de ces travaux de thèse. / Economically developed societies face the problem of an aging population combined with the increase in degenerative diseases. Among the signs of aging, musculoskeletal pathologies (osteoporosis and sarcopenia) are considered major public health problems. Therefore, the development of preventive measures to preserve seniors’ health is a real public health issue. Scientific research provides ample evidence of the importance of diet in diseases reduction or exacerbation. These observations confirm the old concept arguing that the adoption of a balanced diet helps to maintain a healthy life, especially with advancing age. To date, the potential of the olive oil, as such or as a vector of lipophilic nutrients, for the prevention of osteoporosis and sarcopenia, has never been tested. As the prevalence of osteoporosis is much higher in postmenopausal women who also suffer from an accelerated muscle mass loss, this population was targeted in this study. In a first step, original results were obtained regarding the effect of ovariectomy on muscle metabolism. Thus, our work showed that after removal of the ovaries, muscle protein synthesis was reduced in association with a decrease in the expression of a proteolysis marker of this tissue. Taken together, these results suggest a slowing down of muscle protein turnover after ovariectomy. In terms of mechanisms, an increase in lipid tissue infiltration was observed. The slowdown in muscle protein renewal after ovariectomy was associated with an increased bone turnover, classically described in the literature. In a second step, the effect of olive oil and more particularly its polyphenols in combination with vitamin D and docosahexaenoic acid and their possible synergy was assessed using a postmenopausal osteoporosis model. Ovariectomized mice were subjected to one of the following oils: corn oil, refined olive oil, extra virgin olive oil or fish oil. Four additional groups of ovariectomized mice received the oil fortified with vitamin D. This study demonstrated a protective effect of the combination of virgin olive oil and vitamin D on bone loss induced by ovariectomy in mice. Indeed, the acceleration of the bone turnover induced by the estrogen deficiency was inhibited by this combination of nutrients, which also decreased the expression of oxidative stress and inflammation markers. These results are currently being validated in a clinical investigation conducted in postmenopausal women, which has been established during this thesis work.

Environ 5% des patientes sont diagnostiquées chaque année avec un cancer du sein d’emblée métastatique et 20 à 30% des cancers du sein localisés évoluent vers un stade secondairement métastatique. Les bénéfices de l’activité physique pendant les traitements chez les patientes avec un cancer du sein localisé ont largement été démontrés mais la littérature est limitée dans le cancer du sein métastatique. Ce travail de thèse a permis d’évaluer les effets potentiels de l’activité physique chez des patientes atteintes d’un cancer du sein métastatique à travers trois études.L’étude observationnelle StoRM a montré une association du niveau d’activité physique recueilli par questionnaire à une meilleure survie des patientes HER2. L’étude interventionnelle ABLE a mis en évidence la faisabilité d’une intervention en activité physique avec une montre connectée dans cette population avec un excellent taux d’adhérence (96%), l’intérêt et la volonté des patientes pour les programmes d’activité physique ainsi qu’une amélioration fonctionnelle. L’intervention a contribué au un maintien de la qualité de vie, de la fatigue et du niveau d’activité physique malgré les traitements et l’avancée de la maladie. De potentiels biomarqueurs prédictifs d’une progression tumorale ont été identiés. L’étude MUST a montré que l’antioxydant SOD et de la force isométrique d’extension du quadriceps semblent prévenir la sarcopénie et une association entre le statut sarcopénie et le risque de toxicités a été confirmé. Ce travail de thèse représente une première étape dans l’analyse des effets de l’activité physique auprès de patientes atteintes d’un cancer du sein métastatique. L’activité physique semble être bénéfique dans cette population, mais ces résultats nécessitent d’être confirmés dans une étude à plus grande échelle. Ces résultats préliminaires soulignent l’importance de proposer des interventions adaptées en activité physique aux patientes atteintes d’un cancer du sein métastatique dès le diagnostic pour poursuivre un mode de vie actif le plus longtemps possible / Approximately 5% of patients are diagnosed with metastatic breast cancer each year and 20 to 30% of localized breast cancers become secondarily metastatic. Benefits of physical activity during treatment in patients with localized breast cancer have been widely demonstrated, but the literature is limited in metastatic breast cancer. This thesis work assessed the potential effects of physical activity in patients with metastatic breast cancer through three studies.The StoRM observational study showed an association between the level of physical activity collected by questionnaire with an improvement of survival for HER2 patients. The ABLE intervention study highlighted the feasibility of a physical activity intervention with an activity tracker in this population with an excellent adherence rate (96%), patients' interest and willingness to participate in physical activity programs and functional improvements. The intervention contributed to maintaining quality of life, fatigue and physical activity levels despite treatment and disease progression. Potential biomarkers predictive of tumor progression have been identified. The MUST study showed that the antioxidant SOD and quadriceps isometric extension force appear to prevent sarcopenia and an association between sarcopenia status and toxicity risk was confirmed. This thesis work represents a first step in analyzing the effects of physical activity on patients with metastatic breast cancer. Physical activity appears to be beneficial in this population, but these results need to be confirmed in a larger scale study. These preliminary results highlight the importance of providing appropriate physical activity interventions for patients with metastatic breast cancer at the time of diagnosis in order to maintain an active lifestyle as long as possible

The aims of this study were to investigate the mechanisms underlying (1) the ageing-related motor handicap at the whole muscle, cellular, contractile protein and myonuclear levels; and (2) ageing-related differences in muscle adaptability. In vivo muscles function was studied in the knee extensors. Decreases were observed in isokinetic and isometric torque outputs in old age in the sedentary men and women and elite master sprinters. A 20-week long specific sprint and resistance training successfully improved the maximal isometric force and rate of force development in a subgroup of master sprinters. In vitro measurements were performed in muscle biopsies from the vastus lateralis muscle. Immunocytochemical and contractile measurements in single membrane permeabilized muscle fibres demonstrated ageing- and gender-related changes at the myofibrillar level. In sedentary subjects, data showed a preferential decrease in the size of muscle fibres expressing type IIa MyHC in men, lower force generating capacity in muscle fibres expressing the type I MyHC isoform in both men and women and lower maximum velocity of unloaded shortening (V0) in fibres expressing types I and IIa MyHC isoforms in both men and women. The master sprinters also experienced the typical ageing-related reduction in the size of fast-twitch fibres, a shift toward a slower MyHC isoform profile and a lower V0 of type I MyHC fibres, which played a role in the decline in explosive force production capacity. The fast-twitch fibre area increased after the resistance training period. A model combining single muscle fibre confocal microscopy with a novel algorithm for 3D imaging of myonuclei in single muscle fibre segments was introduced to study the spatial organisation of myonuclei and the size of individual myonuclear domains (MNDs). Significant changes in the MND size variability and myonuclear organization were observed in old age, irrespective gender and fibre type. Those changes may influence the local quantity of specific proteins per muscle fibre volume by decreased and/or local cooperativity of myonuclei in a gender and muscle fibre specific manner. In conclusion, the ageing-related impairments in in vivo muscle function were related to significant changes in morphology, contractile protein expression and regulation at the muscle fibre level. It is suggested that the altered myonuclear organisation observed in old age impacts on muscle fibre protein synthesis and degradation with consequences for the ageing-related changes in skeletal muscle structure and function. However, the improved muscle function in response to a 20-week intense physical training regime in highly motivated physically active old subjects demonstrates that all ageing-related in muscle function are not immutable.

Im Rahmen des demographischen Wandels kommt es zu einem kontinuierlichen Anstieg des Anteils postmenopausaler Frauen an der Weltbevölkerung, so dass die Therapie postmenopausaler Erkrankungen zu einem wichtigen Thema der ärztlichen Behandlung geworden ist. Seit Beginn des 21. Jahrhunderts werden hinsichtlich der klinischen Wirksamkeit und der Sicherheit der Hormonersatztherapie vermehrt Bedenken im Hinblick auf das erhöhte Risiko für das kardiovaskuläre System und Brustkrebs geäußert. Aus diesem Grund rücken alternative Therapieansätze verstärkt in den Mittelpunkt der Forschung. In unterschiedlichen Projekten hat sich hierbei CR als effektives, in der klinischen Praxis anwendbares Medikament gezeigt. Die vorliegende Dissertation setzt sich mit der Wirkung von Subfraktionen der Testsubstanz CR auf die klimakterisch bedingten Veränderungen bzw. Erkrankungen der Skelett- und der Herzmuskulatur auseinander. Vor diesem Hintergrund wurden 100 weibliche, zuvor ovariektomierte Sprague-Dawley-Ratten in 10 Gruppen unterteilt und über einen Zeitraum von 4 Wochen die verschiedenen Substanzen von Cimicifuga racemosa (CR) (Saponin-, S1-, S2-, S3-Fraktion und Rest-, R1-, R2- und R3-Fraktion) oder Östradiolbenzoat (EB) verabreicht. Über denselben Zeitraum wurde eine Kontrollgruppe mit sojafreiem Futter versorgt. Mittels histologischer Untersuchung der Herz- und Skelettmuskulatur wurden die Auswirkungen von EB und den verschiedenen Fraktionen und Subfraktionen aus CR ermittelt und untereinander und mit den Ergebnissen der Kontrollgruppe verglichen. Die Skelettmuskelfaserfläche hat unter dem Einfluss der Saponinfraktion, der S1-Subfraktion, der Restfraktion, der R2-Subfraktion und der EB-Gruppe signifikant im Vergleich zur Kontrollgruppe zugenommen. Eine signifikante Zunahme des elastischen Faseranteils bezogen auf die Skelettmuskelfaserfläche bestand unter dem Einfluss der Saponinfraktion, ihrer S1- und S2-Subfraktion und der R1-Subfraktion als auch der EB-Gruppe im Vergleich zur Kontrollgruppe. Die Kardiomyozytenfläche zeigte einen signifikanten Größenzuwachs im Vergleich zur Kontrollgruppe unter dem Einfluss der Saponinfraktion und all ihrer 3 Subfraktionen als auch der Restfraktion und ihrer 3 Subfraktionen und der EB-Gruppe. Eine signifikante Zunahme des elastischen Faseranteils bezogen auf die Kardiomyozytenfläche bestand unter dem Einfluss der Saponinfraktion, ihrer S1-Subfraktion und der Restfraktion und ihrer R3-Subfraktion als auch der EB-Gruppe im Vergleich mit der Kontrollgruppe. Ableiten lässt sich, dass die Subfraktionen der Saponin- und Restfraktion keine gleichmäßige Wirkung auf die strukturellen Bestandteile von Herz- und Skelettmuskulatur zeigen. Die Ergebnisse sprechen dafür, dass bestimmte Subfraktionen von CR anabol auf die Skelettmuskelfaser- und Kardiomyozytenfläche und die EZM beider Gewebe wirken. Nahezu regelmäßig erweist sich die vor allem Actein und Deoxyactein enthaltende S1-Fraktion als wirksamste Substanzgruppe. Die Wirkungen von CR sind noch Gegenstand der aktuellen Forschung. Eines der Ziele weiterer Untersuchungen sollte die Ermittlung der Kombination der jeweiligen Fraktionen und Subfraktionen oder deren Subsubstanzen sein, um eine bestmögliche osteoprotektive und anabole Wirkung auf Herz- und Skelettmuskulatur und den Knochen zur Linderung oder Beseitigung klimakterischer Beschwerden zu entfalten.

Muscle aging, in particular, is characterized by the reduction of tissue mass and function, which are particularly prominent in geriatric individuals undergoing sarcopenia. The age-associated muscle wasting is also associated with a decline in regenerative ability and a reduction in resident muscle stem cell (satellite cell) number and function. Although sarcopenia is one of the major contributors to the general loss of physiological function, the mechanisms involved in age-related loss of muscle homeostasis and satellite cell activity are yet poorly understood. Using a microarray-based transcriptome analysis of muscle stem cells isolated from young and physiologically aged/geriatric mice, we uncovered specific changes in the gene expression profile that highlighted key biological processes and potential molecular markers associated with satellite cell aging, which included p16INK4a. We used Bmi1-deficient mice to further explore the implications of p16INK4a up-regulation in satellite cell function. We found premature p16INK4a up-regulation in young/adult Bmi1-deficient satellite cells correlating with defects in satellite cell number, proliferation and self-renewal capacity. In addition we have identified a number of overlapping biological processes dysregulated in physiologically aged and Bmi1-deficient satellite cells, suggesting that Bmi1-dependent epigenetic regulation may underlie many of the intrinsic changes taking place in chronologically aged satellite cells. In addition, we show that Bmi1 loss causes defects of late postnatal/adult muscle growth characterized by reduced muscle mass with smaller muscle fibers, typical of atrophying senescent/sarcopenic muscle. Since p16INK4a expression is specifically up-regulated in muscle satellite cells of geriatric, sarcopenic mice and in a mouse model of accelerated senescence/sarcopenia (SAMP8), we propose that the Bmi1/p16INK4a axis might be particularly operative in muscle stem cells from the elderly. Muscle wasting is one of the physiological consequences of sarcopenia and the identification of novel factors regulating muscle growth and atrophy is of potential relevance for therapeutical applications. We have uncovered a new role for Sestrins as skeletal muscle growth promoting factors in the adult. We found Sestrins expression regulated in mouse models of skeletal muscle atrophy and hypertrophy and in human myopathies. Through a gain of function approach we show that Sestrins induce skeletal muscle growth, by activating the IGF1/PI3K/AKT pathway. / El envejecimiento del tejido muscular está caracterizado concretamente por una reducción global de la masa muscular y un empeoramiento de la función de tejido, particularmente prominentes en individuos muy viejos (geriátricos) que padecen sarcopenia. La pérdida muscular asociado a la edad, se acompaña de una reducción en la capacidad de regeneración del músculo y en una reducción del número y la función de las células madre residentes en el músculo (células satélite). Aunque la sarcopenia sea una de las causas principales de la pérdida general de función fisiológica del músculo, los mecanismos implicados en la reducción de la homeostasis muscular y de actividad de las células satélite no han sido completamente caracterizados. Mediante el análisis comparativo del transcriptoma de células madre musculares aisladas de ratones jóvenes y de ratones viejos (geriátricos), hemos encontrado cambios específicos en su perfil de expresión génica que apuntan a los procesos biológicos dominantes y a los marcadores moleculares potencialmente asociados con el envejecimiento de las células satélite, entre los que destaca p16INK4a. Por ello, hemos utilizado ratones deficientes en Bmi1 para explorar más profundamente las implicaciones de la sobreexpresión de p16INK4a en la función de las células satélite. Hemos encontrado que células satélite jóvenes del ratón Bmi1-/- presentan sobrexpresión de p16INK4a, que correlacionan con una reducción en el número de la células, y en su capacidad de proliferación y autorenovación. Además hemos identificado un grupo de procesos biológicos comunes entre las células satélite viejas y las deficientes en Bmi1, sugiriendo que la regulación epigenética mediada por Bmi1 puede ser la base de muchos de los cambios intrínsecos que ocurren en células envejecidas fisiológicamente. Además, demostramos que la pérdida Bmi1 causa defectos en el crecimiento postnatal/adulto del músculo, caracterizado por pérdida de masa muscular con fibras más pequeñas, típico del músculo atrofiado senescente o sarcopénico. Puesto que la expresión de p16 está aumentada específicamente en el músculo de ratones viejos, sarcopénicos y en un modelo del ratón con envejecimiento (senescencia) acelerado (SAMP8), proponemos que el eje Bmi1/p16 puede actuar particularmente en las células madre musculares de los ancianos. La pérdida de masa muscular es una de las consecuencias fisiológicas de la sarcopenia y la identificación de nuevos factores que regulen el crecimiento y atrofia del músculo es de gran importancia para aplicaciones terapéuticas. Hemos descubierto un nuevo papel de las Sestrinas como factores promotores del crecimiento del músculo esquelético en el adulto. Hemos encontrado que la expresión de las Sestrinas se regula en modelos del ratón de atrofia y de hipertrofia muscular y en miopatías humanas. Mediante experimentos de ganacia de función hemos demostrado que las Sestrinas inducen el crecimiento del músculo esquelético, activando el ruta de señalización de IGF1/PI3K/AKT

Submitted by Automa??o e Estat?stica (sst@bczm.ufrn.br) on 2017-08-10T11:59:48Z No. of bitstreams: 1 LeonidasDeOliveiraNeto_TESE.pdf: 1668906 bytes, checksum: 3fa7c80c1f7980340ddded1cd5fc5726 (MD5) / Approved for entry into archive by Arlan Eloi Leite Silva (eloihistoriador@yahoo.com.br) on 2017-08-11T15:48:54Z (GMT) No. of bitstreams: 1 LeonidasDeOliveiraNeto_TESE.pdf: 1668906 bytes, checksum: 3fa7c80c1f7980340ddded1cd5fc5726 (MD5) / Made available in DSpace on 2017-08-11T15:48:54Z (GMT). No. of bitstreams: 1 LeonidasDeOliveiraNeto_TESE.pdf: 1668906 bytes, checksum: 3fa7c80c1f7980340ddded1cd5fc5726 (MD5) Previous issue date: 2017-06-05 / Introdu??o: O diagn?stico da sarcopenia ? restrito aqueles com boa capacidade f?sica e cognitiva, n?o sendo adaptado ?s condi??es dos idosos institucionalizados. Al?m disso, apesar da perda de massa muscular ser determinante para seu diagn?stico, redu??o associada de massa gorda tem sido observada na sarcopenia. Ademais, embora o estado inflamat?rio seja considerado um gatilho da perda de massa muscular, a redu??o no tecido adiposo tem sido associado ? redu??o do estado inflamat?rio, concorrendo no constructo te?rico da associa??o entre inflamm-aging e sarcopenia. Objetivo: Discutir o diagn?stico para sarcopenia em idosos institucionalizados e verificar a associa??o entre inflamm-aging e sarcopenia, assim como analisar seus fatores associados. Metodologia: Tr?s estudos foram conduzidos em idosos de ambos os sexos, residentes em institui??es de longa perman?ncia na cidade do Natal/RN. No estudo 1 (n=219) foi realizado uma adapta??o do Consenso Europeu para Diagn?stico da Sarcopenia (2010) agregando idosos com baixa capacidade f?sica e cognitiva. No estudo 2 (n=219) foi verificado quais os fatores est?o associados ? sarcopenia. No estudo 3 (n=187) foi realizado an?lise de conglomerados de idosos segundo seu estado inflamat?rio e verificado os fatores associados ? esta condi??o. Resultados: Inclus?o de idosos com baixa condi??o f?sica e cognitiva (estudo 1) acresceu em 32,2% a preval?ncia de sarcopenia. No estudo 2, os fatores associados ? sarcopenia foram altura do joelho, eutrofia e excesso de peso (segundo IMC) e capacidade de deambular. No estudo 3 foi poss?vel verificar que aumento de 1 unidade ?g/dL no LDL, HDL e triglicer?deos apresentaram aumento de 1,5%, 4,1% e 0,9% a chance de inflamm-aging e idosos longevos (?80 anos) possu?ram 84,9% mais de chance de inflamm-aging. Conclus?o: Inclus?o de idosos com baixa capacidade f?sica e cognitiva para c?lculo de sarcopenia ? valida e representa de modo mais adequado os idosos institucionalizados, apresentando o aspectos antropom?tricos e f?sicos como seus principais fatores associados. Ademais, os indicadores bioqu?micos e antropom?tricos demonstraram rela??o da sarcopenia com desnutri??o. Al?m disso, n?o foi observado associa??o do inflamm-aging com sarcopenia, corroborando o constructo de que na sarcopenia n?o ocorre perda seletiva da massa muscular. / Introduction: The diagnosis of sarcopenia is restricted to those with good physical and cognitive capacity, not being adapted to the conditions of the institutionalized elderly. In addition, dispite the loss of muscle mass is determinant for its diagnosis, associated reduction of fat mass has been observed in sarcopenia. Although the inflammatory state is considered a trigger to loss of muscle mass, reduction in adipose tissue has been associated with the reduction of the inflammatory state, competing in the theoretical construct of the association between inflammation and sarcopenia. Objective: To discuss the diagnosis of sarcopenia in institutionalized elderly patients and to verify the association between inflammation and sarcopenia, as well as to analyze their associated factors. Methodology: Three studies were conducted in elderly people of both sexes, living in nursing homes in the city of Natal / RN. In study 1 (n = 219) an adaptation of the European Consensus for Diagnosis of Sarcopenia (2010) was carried out, adding elderly people with low physical and cognitive capacity. In study 2 (n = 219) it was verified which factors are associated with sarcopenia. In study 3 (n = 187), the analysis of elderly conglomerates according to their inflammatory state was performed and the factors associated with this condition were verified. Results: Inclusion of elderly people with low physical and cognitive status (study 1) increased the prevalence of sarcopenia by 32.2%. In study 2, the factors associated with sarcopenia were knee height, eutrophy and excess weight (according to BMI) and the ability to ambulate. In study 3 it was possible to verify that increase of 1 unit ?g / dL in LDL, HDL and triglycerides presented a 1.5%, 4.1% and 0.9% increase in the chance of inflamm-aging and elderly individuals (?80 years ) had an 84.9% greater chance of inflammation. Conclusion: Inclusion of elderly with low physical and cognitive capacity to calculate sarcopenia is valid and represents more appropriately the institutionalized elderly, presenting the anthropometric and physical aspects as their main associated factors. In addition, the biochemical and anthropometric indicators demonstrated a relationship of sarcopenia with malnutrition. In addition, no association of inflammation with sarcopenia was observed, corroborating the construct that in sarcopenia there is no selective muscle mass loss.

Sarcopenia is a disease of muscle wasting primarily seen in older adults. Although this term was first coined over three decades ago, there is a lack of consensus on a definition, screening criteria, and treatment protocol for sarcopenia. The primary purpose of this study is to determine whether registered dietitian nutritionists (RDNs) in the United States (U.S.) screen for sarcopenia. Study participants were recruited through a randomized email list and included RDNs throughout the U.S. Respondents completed a survey questioning knowledge of sarcopenia, screening tools and company protocols in place, and the need and desire for sarcopenia education. Data revealed a lack of pre-existing protocols in place, a dissonance of validated and unvalidated screening tools used in practice, and substantial need for sarcopenia education.

In recent years, the transplant community has explored and adopted tools for quantifying clinical insight into illness severity and frailty. This dissertation work explores the interplay between objective and subjective assessments of physical health status and the implications for liver transplant candidate and recipient outcomes. The first aim characterizes national epidemiologic trends and the impact of Centers for Medicare and Medicaid quality improvement policies on likelihood of waitlist removal based on the patient being too frail to benefit from liver transplant (“too sick to transplant”). This aim includes more than a decade (2002–2012) of comprehensive national transplant waitlist data (Scientific Registry of Transplant Recipients (SRTR)). The second aim will assess and define objective parameters of liver transplant patient frailty by measuring decline in lean core muscle mass (“sarcopenia”) using abdominal CT scans collected retrospectively at a single U.S. transplant center between 2006 and 2015. The relationship between these objective sarcopenia measures and subjective functional status assessed using the Karnofsky Functional Performance (KPS) scale are described and quantified. The third aim quantifies the extent to which poor functional status (KPS) pre-transplant is associated with worse post-transplant survival and includes national data on liver transplantations conducted between 2005 and 2014 (SRTR). The results of this dissertation will help providers in the assessment of frailty and subsequent risk of adverse outcomes and has implications for strategic clinical management in anticipation of surgery. This research will also to serve to inform national policy on the design of transplant center performance measures.