Skeletal muscles are highly resilient due to the capacity to regenerate damaged muscle tissue. Despite the regenerative capacity, pathological conditions can lead to reduced muscle mass and... Show moreSkeletal muscles are highly resilient due to the capacity to regenerate damaged muscle tissue. Despite the regenerative capacity, pathological conditions can lead to reduced muscle mass and strength, also known as muscle wasting. Muscle wasting, seen in pathological conditions, is often progressive and concomitant with excessive or prolonged inflammation, fibrosis and fat infiltration. Aging is a risk factor for a large number of diseases that can result in muscle wasting. The prevalence of sarcopenia, an age-associated decline in skeletal muscle mass and strength in elderly, surges as life expectancy increases. In combination with muscle wasting caused by neuromuscular disorders, the burden of muscle wasting on society is significant. Gaining a better understanding of the cellular and molecular processes underlying muscle wasting conditions is critical for creating better treatments. Aging and thereby age-associated muscle wasting are multifactorial involving changes in different tissues and multiple cell systems. This thesis demonstrates how different omics approaches, like transcriptomics, proteomics and metabolomics, can elucidate the complexity of those molecular mechanisms and cellular processes involved in muscle wasting conditions. Employing a combination of different omics-techniques (multi-omics) specifically proved powerful and will continue to illuminate impaired mechanisms and consequently help to battle muscle wasting. Show less
Epigenetic regulation of gene expression by chromatin modifiers is one of the fundamental cellular processes that allow the different cell types in the body to develop from the totipotent embryonic... Show moreEpigenetic regulation of gene expression by chromatin modifiers is one of the fundamental cellular processes that allow the different cell types in the body to develop from the totipotent embryonic stem cells. However, when this epigenetic control mechanism becomes compromised, such as by mutations in chromatin modifiers, it can lead to the development of disease. An example of such epigenetic disease is facioscapulohumeral muscular dystrophy (FSHD), in which the chromatin structure of the D4Z4 macrosatellite repeat is compromised. The loss of a repressive D4Z4 chromatin structure either by contraction of the repeat to a size of 1-10 D4Z4 units (FSHD1), or by mutations in D4Z4 chromatin repressors such as SMCHD1 (FSHD2), results in inappropriate expression of the DUX4 gene from the repeat in skeletal muscle, which is considered the root cause of FSHD.In FSHD, DUX4 expression causes apoptosis, leading to muscle wasting in the patient. In this thesis, we studied the functionality of SMCHD1, and aimed to understand the DUX4 repressive processes in which SMCHD1 is involved. Furthermore, we gathered information on the different roles that SMCHD1 fulfills, such as X-chromosome inactivation in female cells and telomere maintenance. Show less
