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Molecular underpinning of age-related muscle loss

Research Project
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01.01.2016
 - 31.12.2018

Skeletal muscle is the largest organ of the human body and thus, it has essential roles that include not only locomotion and breathing, but also in the regulation of energy and glucose homeostasis in the entire body. Skeletal muscle wasting is associated with a wide range of conditions, including heart and kidney failure, as well as cancer. Muscle wasting is also a hallmark of many, rare neuromuscular diseases. As the average life span in the human population increased, the loss of muscle mass and function at high age, called sarcopenia, has become an important socio-economic challenge of civilized countries. Sarcopenia is the main cause of frailty and leads to a high frequency of falls in the elderly. Sarcopenia is characterized by many morphological alterations of the skeletal muscle such as atrophy, changes in oxidative properties and degeneration combined with a poor regenerative capacity. Moreover, the site of contact between motor neurons and skeletal muscle fiber, called the neuromuscular junction, becomes fragmented indicating impaired function. Although multiple factors such as hormonal changes (e.g. testosterone, oestrogen, growth hormone, IGF-1), changes in muscle proteostasis (i.e. balance between anabolic and catabolic pathways) and in mitochondrial function have been implicated in sarcopenia, the underlying molecular mechanisms are not at all understood. In addition, extrinsic factors such as daily activity and nutritional habits have been shown to affect sarcopenia. In this Sinergia project, we aim to identify the core pathways underlying sarcopenia by conducting a multi-level analysis of mouse models that cover a broad range of rates at which the sarcopenic phenotype develops. Specifically, we will examine the aging process longitudinally in mice undergoing natural aging, two very distinct transgenic mouse models that both (muscle-specific TSC and Klotho knockouts) show accelerated sarcopenia, as well as mice that were subjected to treatments that were shown to prolong lifespan and delay sarcopenia. These are caloric restriction, exercise, treatment with rapamycin or transgenic expression of PGC-1a. With state-of-the-art methods for estimating mRNA transcription, mRNA translation and protein degradation rates we will evaluate proteostasis and signaling pathways implicated in sarcopenia in the muscles of all these mouse groups. We will extend this analysis to specific sub-cellular compartments such as the mitochondria and the neuromuscular junction, whose function has been found crucial for the maintenance of muscle functionality. In spite of a strong resurgence of interest in aging and aging-related conditions, the vast majority of the studies that have been done to date focused on a limited set of conditions or pathways. Substantial effort has been put in the physiological characterization of the animal models, but quantitative, genome-wide studies are scarce and largely limited to the transcriptomic level. The main strengths of our project are that 1. we will study in parallel mouse models in which the progression to sarcopenia is modulated through distinct, but presumably interlinked pathways; 2. we will apply a simultaneous and comprehensive analysis of all models, with a homogeneous set of state-of-the art methods that we have at our disposal through the highly complementary expertise of the groups involved. This will allow us to assess the relative contributions of individual pathways to the different phenotypes as well as distill a core signature of sarcopenia. Importantly, the comprehensiveness of the genome-wide data that we will obtain and analyze computationally will enable us to uncover novel regulators of muscle function in health and disease.

Funding

Molecular underpinning of age-related muscle loss

SNF Projekt (GrantsTool), 11.2015-10.2018 (36)
PI : Rüegg, Markus A..
CI : Handschin, Christoph,Zavolan, Mihaela.

Publications

Börsch, Anastasiya and Zavolan, Mihaela (2021) ‘Transcription factor motif activity as a biomarker of muscle aging’, American journal of aging science and research, 2(1), pp. 19–23.

URLs
URLs

Ham, Daniel J. et al. (2020) ‘The neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia’, Nature Communications, 11(1), p. 4510. Available at: https://doi.org/10.1038/s41467-020-18140-1.

URLs
URLs

Gill, Jonathan F. et al. (2018) ‘PGC-1α affects aging-related changes in muscle and motor function by modulating specific exercise-mediated changes in old mice’, Aging Cell, 17(1), p. e12697. Available at: https://doi.org/10.1111/acel.12697.

URLs
URLs

Members (9)

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Markus A. Rüegg

Principal Investigator
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Christoph Handschin

Co-Investigator
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Mihaela Zavolan

Co-Investigator
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Meric Ataman

Project Member
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Anastasiya Börsch

Project Member
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Julien Delezie

Project Member
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