Skeletal muscle is one of the most abundant tissues in the body and makes up over 40% of the total body mass. It is important for mobility and posture maintenance as well as plays a central role in whole body metabolism. Skeletal muscle is made up of bundles of muscle fibers, which in turn have bundles of myofibrils inside them. Thus, structurally skeletal muscle has a very defined and striking organization. Moreover, based on their mode of respiration, there can be different types of muscle fibers. Despite having such an organized structure, one of the most fascinating properties of skeletal muscle is that it is highly adaptable to environmental stimuli, including exercise, nutrient availability and cold temperature. Based on the type of external stimuli, muscle can respond either by shifting its fiber type composition or by altering the fiber size. Thus, the dynamic nature of skeletal muscle is useful for adapting to changes in environmental conditions and consequently is also linked to a number of disease conditions like atrophy, insulin resistance, diabetes, sarcopenic obesity, and others. However, the exact molecular and genomic mechanisms regulating skeletal muscle plasticity are not fully understood. To this end, my thesis has focused on trying to understand the dynamic nature of skeletal muscle at the epigenomic level. I first used a top down unbiased sequencing approach to define the in vivo skeletal muscle epigenomic architecture and also establish how these enhancers patterns change with genetic or exercise-induced fiber type transformations. This led to identification of novel transcriptional regulators of exercise reprogramming. In a separate project, I used a targeted approach to define the role of a transcription factor, BCL6, in skeletal muscle metabolism and mass maintenance. BCL6 was found to control muscle mass by maintaining a balance between protein synthesis and degradation, and its deletion reduced the rate of protein synthesis, by direct de-repression of key negative regulators of protein synthesis. Taken together, this work demonstrates that in addition to a rapidly changing proteome and transcriptome, a highly dynamic enhancer landscape is critical for the adaptable nature of skeletal muscle and highlights the importance of understanding muscle plasticity at the epigenomic level.

Creator

• Ramachandran, Krithika

DOI

• https://doi.org/10.21985/n2-bd1z-j315

Subject

• Molecular biology
• Endocrinology

Language

• en

Alternate Identifier

• etdadmin_upload_718262
• http://dissertations.umi.com/northwestern:14993

Keyword

• Muscle plasticity
• Genomics
• ChIP-seq
• Muscle atrophy

Date created

• 2020-01-01

Resource type

• Dissertation

Rights statement

• In Copyright