Date of Award

2017

Document Type

Open Access Dissertation

Department

Exercise Science

Sub-Department

Norman J. Arnold School of Public Health

First Advisor

James A. Carson

Abstract

Maintaining skeletal muscle mass has a well-documented role in health and quality of life. Two members of IL-6 family of cytokines, IL-6 and LIF, and have a paradoxical role in skeletal muscle mass regulation: short term elevation of IL-6 and LIF plays a key role in mechanical stimuli induced muscle growth and muscle hypertrophy, while the long term elevated IL-6 and LIF regulate muscle wasting during cancer cachexia by disrupting muscle protein turnover regulation. The regulation of muscle protein synthesis is an important determinant of mechanical stimuli induced muscle hypertrophy and muscle wasting during cancer cachexia. IL-6 family of cytokines can induce intracellular signaling pathways involved in muscle mass regulation, including STAT3, ERK1/2, PI3K/Akt and AMPK via their functional receptor complex containing gp130. However, it is still unknown whether physiologically and pathologically elevated IL-6 or LIF can regulate basal mechanical stimuli induced muscle protein synthesis. The overall purpose of this dissertation was to determine if physiological short term or pathological long term exposure of IL-6 and LIF would regulate basal protein synthesis or protein synthesis induction by mechanical stimuli in cultured myotubes and skeletal muscles. Specific aim 1 investigated if physiological short term exposure of IL-6 or LIF would activate myotube protein synthesis by activating gp130-Akt-mTOR signaling cascade. Short term IL-6 and LIF exposure increased myotube protein synthesis, which was associated with the induction of gp130-Akt signaling pathway. Either gp130 siRNA knock-down or Akt signaling inhibition blocked IL-6/LIF induction of myotube protein synthesis, Interestingly, mTORC1 or STAT3 signaling inhibition did not completed blocked IL-6/LIF induction of myotube protein synthesis. Specific aim 2 investigated if pathological long term IL-6 or LIF exposure would suppress myotube protein synthesis by activating AMPK signaling. We reported long term exposure of IL-6 and LIF suppressed myotube mTORC1 signaling and protein synthesis, which was rescued by the pharmaceutical inhibition of AMPK signaling during IL-6/LIF exposure. However, long term AMPK signaling resulted suppression of basal myotube protein synthesis. Specific aim 3 investigated if short term or long term IL-6/LIF exposure would regulate stretch induction of protein synthesis in myotubes and eccentric contraction induction of protein synthesis in skeletal muscles, respectively. We reported that both short term and long term IL-6/LIF disrupted stretch induction of myotube protein synthesis in vitro, but in vivo IL-6 overexpression had no effect on muscle protein synthesis induction by eccentric contractions. Taken together, our results demonstrate that short term IL-6 or LIF exposure can stimulate protein synthesis in myotubes by activating gp130-Akt signaling, but is not dependent on mTOR signaling. Long term pathological exposure of IL-6 or LIF suppressed myotube protein synthesis though the activation of AMPK signaling. However, the IL-6/LIF regulation of mechanical stimulus induction of protein synthesis is dependent on different mechanical stimuli models. These findings provide new insight of the IL-6/LIF role in skeletal muscle mass regulation under physiological and pathological conditions.

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