Cancer cachexia-induced muscle atrophy: evidence for alterations in microRNAs important for muscle size.
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. Multiple microRNAs (miRNAs) have been identified as being involved in muscle development and atrophy; however, less is known specifically on miRNAs in cancer cachexia. The purpose of this investigation was to examine the miRNA profile of skeletal muscle atrophy induced by cancer cachexia to uncover potential miRNAs involved with this catabolic condition. Phosphate-buffered saline (PBS) or Lewis lung carcinoma cells (LLC) were injected into C57BL/6J mice at 8 wk of age. LLC animals were allowed to develop tumors for 4 wk to induce cachexia. Tibialis anterior muscles were extracted and processed to isolate small RNAs, which were used for miRNA sequencing. Sequencing results were assembled with mature miRNAs, and functions of miRNAs were analyzed by Ingenuity Pathway Analysis. LLC animals developed tumors that contributed to significantly smaller tibialis anterior muscles (18.5%) and muscle cross-sectional area (40%) compared with PBS. We found 371 miRNAs to be present in the muscle above background levels. Of these, nine miRNAs were found to be differentially expressed. Significantly altered groups of miRNAs were categorized into primary functionalities including cancer, cell-to-cell signaling, and cellular development among others. Gene network analysis predicted specific alterations of factors contributing to muscle size including Akt, FOXO3, and others. These results create a foundation for future research into the sufficiency of targeting these genes to attenuate muscle loss in cancer cachexia.
Integrative Muscle Metabolism Laboratory, University of Arkansas, Fayetteville, Arkansas.
David E
DE
Lee
Integrative Muscle Metabolism Laboratory, University of Arkansas, Fayetteville, Arkansas.
Jacob L
JL
Brown
Integrative Muscle Metabolism Laboratory, University of Arkansas, Fayetteville, Arkansas.
Megan E
ME
Rosa-Caldwell
Integrative Muscle Metabolism Laboratory, University of Arkansas, Fayetteville, Arkansas.
Thomas A
TA
Blackwell
Exercise Muscle Biology Laboratory, Department of Health, Human Performance, and Recreation, University of Arkansas, Fayetteville, Arkansas.
Richard A
RA
Perry
Exercise Muscle Biology Laboratory, Department of Health, Human Performance, and Recreation, University of Arkansas, Fayetteville, Arkansas.
Lemuel A
LA
Brown
Department of Poultry Science, University of Arkansas, Fayetteville, Arkansas; and.
Bhuwan
B
Khatri
Department of Poultry Science, University of Arkansas, Fayetteville, Arkansas; and.
Dongwon
D
Seo
Department of Poultry Science, University of Arkansas, Fayetteville, Arkansas; and.
Walter G
WG
Bottje
Exercise Muscle Biology Laboratory, Department of Health, Human Performance, and Recreation, University of Arkansas, Fayetteville, Arkansas.
Tyrone A
TA
Washington
Department of Health and Kinesiology, University of Texas at Tyler, Tyler, Texas.
Michael P
MP
Wiggs
Department of Poultry Science, University of Arkansas, Fayetteville, Arkansas; and.
Byung-Whi
BW
Kong
Integrative Muscle Metabolism Laboratory, University of Arkansas, Fayetteville, Arkansas; npgreene@uark.edu.
Nicholas P
NP
Greene
D000818:Animals; D002100:Cachexia / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology*; D009133:Muscular Atrophy / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D009374:Neoplasms, Experimental / Q000150:complications / Q000235:genetics*
D035683:MicroRNAs
cachexia; miRSeq; muscle wasting