H2020Индивидуална стипендия2016–2018

LYSOTRACK · Defining the role of lysosomal trafficking in age-associated anabolic resistance in human skeletal muscle

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2016-09-01 → 2018-08-31
Финансиране от ЕС: 195 455 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Механизмите на транспорт в лизозомите се изследват, за да се разбере защо мускулите на възрастните хора не растат ефективно след спорт или прием на протеини. Това помага за разбирането на саркопения – загубата на мускулна маса и сила при стареенето.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Defining the role of lysosomal trafficking in age-associated anabolic resistance in human skeletal muscle

Ageing is associated with a progressive loss of skeletal muscle mass and strength, which ultimately results in a condition termed as sarcopenia. While variable between individuals, typically, muscle mass remains relatively stable until the age of ~50 years, after which it deteriorates at a rate of approximately 0.5-1% per year. However, associated losses in muscle strength occur more rapidly which results in older muscles becoming disproportionately weak. Sarcopenia occurs independently of health status and leads to increased frailty, loss of mobility, an increased risk of falls and fractures, a diminished quality of life, and in some cases, premature mortality. Maintenance or growth of muscle mass is mainly driven by increased muscle protein synthesis (i.e. the generation of new muscle protein) in response to exercise and consumption of high-quality proteins rich in essential amino acids. However, several studies have shown that elderly individuals have a blunted protein synthesis response following amino acid administration. Similarly, the elderly also elicit a dampened protein synthesis response following resistance exercise, compared to the young. This inability of the elderly to properly respond to growth-promoting (i.e. anabolic) stimuli has been termed anabolic resistance and plays a significant role in the development of sarcopenia. However, while age-associated anabolic resistance is a well-established physiological phenomenon, the precise mechanisms underpinning anabolic resistance are unknown. At the molecular level, skeletal muscle protein synthesis is primarily regulated by a protein complex called mTOR Complex 1 (mTORC1). The precise mechanisms by which anabolic stimuli activate mTORC1 in humans are not known, however recent studies in cells have identified the lysosome as a being vital for the activation of mTORC1 and thus, protein synthesis. The lysosome is the organelle within cells responsible for breaking down proteins and recycling the amino acids (i.e. the building blocks of proteins). Lysosomes have the ability to move from one part of the cell to another, and based on recent evidence, this lysosomal movement (i.e. lysosomal trafficking) in itself, seems to be vital for the activation of protein synthesis. Thus, age-associated impairments in the movement of lysosomes within aged muscle cells, may represent a possible explanation for the development of anabolic resistance in elderly individuals. Therefore the primary aim of this project was to examine the involvement of lysosomal movement in the regulation of protein synthesis in human skeletal muscle in the context of age-associated anabolic resistance.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

The reduced ability of skeletal muscle to grow, termed anabolic resistance (AR), is thought to be a major cause of age-associated muscle loss (sarcopenia). At the cellular level, AR is caused by an impaired activation of the protein kinase mTORC1, which in turn blunts protein synthetic responses to anabolic stimuli. Lysosomal trafficking is critical for the full activation of mTORC1, with the blocking of this event creating anabolic resistance in otherwise healthy cells. However, to date, this phenomenon has not been examined in human skeletal muscle. Therefore, our working hypothesis is that alterations in lysosomal trafficking may be an underlying mechanism to explain impaired mTORC1 activity and AR in elderly individuals. To address this hypothesis, we will define, for the first time, the role and regulation of lysosomal trafficking in age-associated AR in human skeletal muscle. Through a combination of in-vitro and in vivo studies we will examine (1) whether genetic induction of lysosomal trafficking can activate mTORC1 and overcome chemical/nutrient induced AR in human primary myotubes, (2) whether genetic knockdown of proteins that stimulate lysosomal trafficking can inhibit mTORC1 activity and cause AR, and (3) examine whether lysosomal trafficking differs between young and elderly subjects, in vivo, in response to anabolic stimuli such as amino acids and resistance exercise.The importance of this work should not be understated, given that the number of individuals aged over 60 and 80 years is expected to triple and quadruple respectively by 2050. By advancing the understanding of why elderly individuals exhibit AR and how this phenomenon may contribute to the development of sarcopenia, the work proposed herein has great potential for the development of novel therapeutic approaches to prevent or reduce the occurrence of AR, reduce the severity of sarcopenia which in turn will dramatically improve quality of life.

Оригинален текст от CORDIS (на английски).

Участници

THE UNIVERSITY OF BIRMINGHAM · BirminghamКоординаторОбединеното кралство