Understanding roles for PARP1 in skeletal muscle

Tan, A., 2023. Understanding roles for PARP1 in skeletal muscle. PhD, Nottingham Trent University.

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Abstract

Depletion of Nicotinamide adenine dinucleotide (NAD+), a critical cofactor in biochemical reactions, is ascribed to metabolic dysfunction and poor quality of life. The NAD+ consuming enzyme Poly-(ADP-ribose) polymerase 1 (PARP1) generates ADP-ribose (ADPR), applied as a form of post-translational modification termed Poly (ADP-ribosyl)ation (PARylation), crucial for genome maintenance. However, recent work has ascertained further roles including energy homeostasis and cellular identity.

This work aimed to identify PARP1 mediated PARylation within skeletal muscle myoblast cell lines that undergo myogenesis into myotubes. PARP1 PARylation was inhibited at the start of myogenesis to ascertain its dynamics and impacts throughout myogenesis. Further downstream impacts of PARP1 inhibited differentiated myotubes were investigated using proteomic and transcriptomic approaches. PARP1 and PAR dynamics within tissues of mice subjected to various metabolic challenges were also assessed.

While not fundamental for myotube development, myotubes subjected to PARP1 inhibition at the start of myogenesis exhibited impacts on expression of genes and proteins key for structure and function, and additionally, the transcriptional response to glucocorticoids. These underscore PARP1 impacts in pathways mutual to actions of glucocorticoids, which act as regulators of skeletal muscle mass, myogenesis and atrophy, as well as protein metabolism.

Overall, this work highlights how PARP1 mediated PARylation impacts skeletal muscle homeostasis – mechanisms crucial to mass maintenance and endocrine response.

Item Type:	Thesis
Creators:	Tan, A.
Date:	January 2023
Divisions:	Schools > School of Science and Technology
Record created by:	Linda Sullivan
Date Added:	12 Sep 2023 10:32
Last Modified:	12 Sep 2023 10:32
URI:	https://irep.ntu.ac.uk/id/eprint/49685

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