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Dissertation Meghna Pant OSBP.pdf (2.25 MB)

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SLN Upregulation and Metabolic Alterations: An Underlying Theme during Cold Stress, Infection and Muscle Dystrophy

Pant, Meghna
http://rave.ohiolink.edu/etdc/view?acc_num=osu1429289771

Abstract Details

2015, Doctor of Philosophy, Ohio State University, Biochemistry Program, Ohio State.
Sustaining the metabolic needs of skeletal muscle is essential for maintaining normal muscle function. Skeletal muscle displays remarkable metabolic flexibility in terms of substrate utilization and under conditions of metabolic stress it can provide glucose and amino acids to other organs. Since it is a major sink for substrates, alterations in muscle metabolism are known to result in metabolic disorders and muscle diseases. Therefore, understanding the regulation of skeletal muscle metabolism is central to identifying therapeutic targets for a myriad of diseases. We recently identified that Sarcolipin (SLN) a regulator of Sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) plays an important role in skeletal muscle metabolism and muscle based thermogenesis. It has also been shown that SLN promotes uncoupling of SERCA leading to heat production in vitro but the mechanism behind the regulation of its expression remains largely unknown. Here, we show that SLN expression is developmentally regulated in mice. Interestingly, cold acclimatization overrides the developmental downregulation of SLN indicating the importance of muscle-based thermogenesis in neonates. We further demonstrate that pathological conditions like salmonella infection, inflammation and muscle disease like Duchenne muscular dystrophy upregulate SLN expression in skeletal muscle. All these physiological and pathological states are accompanied by alterations in metabolic machinery, increase in energy expenditure and metabolic stress. We demonstrate that glycolytic enzyme isoforms like hexokinase 1 and pyruvate kinase M2 are upregulated during these conditions triggered by completely different stimuli. In addition the expression of regulators of mitochondrial dynamics like mitofusin 2 and dynamin related protein 1 are altered during these pathophysiological states further indicating that the skeletal muscle is under severe metabolic stress and is trying to adapt. Interestingly, we show that synthetic glucocorticoid dexamethazone upregulates SLN expression in skeletal muscle cells suggesting that stress hormone glucocorticoids may upregulate SLN expression during these different conditions that impose metabolic stress on skeletal muscle. Our studies with SLN overexpression mice indicate that SLN promotes mitochondrial biogenesis and oxidative metabolism during conditions of metabolic overload like high fat diet. To further confirm those findings we overexpress SLN in C2C12 myotubes and show that SLN promotes oxidative metabolism and inhibits glycolysis. Collectively, our data shows the plasticity of the skeletal muscle in altering its metabolic needs during severe physiological or pathological conditions. We demonstrate for the first time that metabolic stress imposed by various external agents (cold, bacterial infection, endotoxin) upregulates SLN expression in skeletal muscle possibly via glucocorticoid signaling. Our data highlights that SLN is recruited not only in cold induced thermogenesis but also in diverse pathological states that may impose metabolic stress on skeletal muscle. The upregulation of SLN expression under these conditions suggests that regulation of calcium cycling in skeletal muscle may help mediate the accompanying metabolic changes to cope up with the increase/altered demands.
Muthu Periasamy (Advisor)
Jill Rafael-Fortney (Committee Member)
Denis Guttridge (Committee Member)
Martha Belury (Committee Member)
131 p.
Biochemistry; Physiology
Sarcolipin, SERCA, thermogenesis, skeletal muscle metabolism, muscle dystrophy

Recommended Citations

Citations

  • Pant, M. (2015). SLN Upregulation and Metabolic Alterations: An Underlying Theme during Cold Stress, Infection and Muscle Dystrophy [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429289771

    APA Style (7th edition)

  • Pant, Meghna. SLN Upregulation and Metabolic Alterations: An Underlying Theme during Cold Stress, Infection and Muscle Dystrophy. 2015. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1429289771.

    MLA Style (8th edition)

  • Pant, Meghna. "SLN Upregulation and Metabolic Alterations: An Underlying Theme during Cold Stress, Infection and Muscle Dystrophy." Doctoral dissertation, Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429289771

    Chicago Manual of Style (17th edition)

osu1429289771
551
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This open access ETD is published by The Ohio State University and OhioLINK.