CANCER CACHEXIA-INDUCED MUSCLE ATROPHY: EVIDENCE FOR ALTERATIONS IN MICRORNAS IMPORTANT FOR MUSCLE SIZE
David E. Lee1, Jacob L. Brown1, Megan E. Rosa-Caldwell1, Richard A. Perry, Jr.1, Lemuel A. Brown1, Bhuwan Khatri1, Dongwon Seo1, Tyrone A. Washington1, Michael P. Wiggs2, Byung-Whi Kong1 & Nicholas P. Greene1. 1University of Arkansas, Fayetteville, Arkansas; 2University of Texas at Tyler, Tyler, Texas
Muscle atrophy is a hallmark of cancer-cachexia resulting in impaired function and quality of life and cachexia is the immediate cause of death for 20-40% of cancer patients. The resulting atrophy leads to a decreased functional ability of the muscle, therefore, muscle atrophy developed during cancer-cachexia leads to an exacerbation in the functional decline of cancer patients. microRNAs regulate to translation of specific mRNAs, and are implicated in regulation of muscle size. The impact of cancer-cachexia on the microRNA profile is poorly understood. PURPOSE: The purpose of this investigation was to examine the miRNA profile of skeletal muscle atrophy induced by cancer-cachexia in order to uncover potential miRNAs involved with this catabolic condition. METHODS: Two groups of C57BL/6J mice were either injected with sterile phosphate buffered saline (PBS) or LLC1 lung carcinoma cells into the dorsal flank. After four weeks, LLC1 mice developed cancerous tumors and cachexia. Hindlimb muscles were collected, snap frozen and processed to isolate pure high quality, short RNAs. RNAs were analyzed using miRSEQ microRNA sequencing and data was analyzed using Ingenuity Pathway Analysis. RESULTS: Tumor weights were ~3.3g in LLC1 compared to 0g in PBS mice. Tibialis Anterior (18%), Gastrocnemius (7%), and Epididymal Fat (10%) were all lower weight in LLC1 compared to PBS (p<0.05) verifying cachexia. Three hundred seventy-two distinct microRNAs were identified as being expressed in the tissue. Nine of these miRNAs were significantly different between groups (p<0.05), and 20 total miRNAs were identified as being altered between LLC1 and PBS at the p<0.10 level. These miRNAs were classified as playing a role in numerous physiological processes and intracellular signaling pathways such as those involved with cell cycle progression (MYC) and cellular growth (Akt) among others. CONCLUSION: This investigation has taken clear steps to discover novel alterations in microRNAs in the context of cancer-cachexia-induced muscle atrophy and potential mechanisms involved in the onset of both cachexia and possibly other forms of muscle atrophy. Future experiments can be designed to identify specific cellular necessity and sufficiency of these microRNAs in maintenance of muscle size as possible therapeutics for muscle atrophy.
(This investigation was funded by the Arkansas Bioscience Institute)
Lee, DE; Brown, JL; Rosa-Caldwell, ME; Perry Jr., RA; Brown, LA; Khatri, B; Seo, D; Washington, TA; Wiggs, MP; Kong, BW; and Greene, NP
"CANCER CACHEXIA-INDUCED MUSCLE ATROPHY: EVIDENCE FOR ALTERATIONS IN MICRORNAS IMPORTANT FOR MUSCLE SIZE,"
International Journal of Exercise Science: Conference Proceedings: Vol. 11:
4, Article 24.
Available at: https://digitalcommons.wku.edu/ijesab/vol11/iss4/24