Myogenetic Oligodeoxynucleotide Restores Differentiation and Reverses Inflammation of Myoblasts Aggravated by Cancer-Conditioned Medium

Abstract

Cancer cachexia is characterized by irreversible muscle loss which is a critical factor in the prognosis of cancer patients. Myoblasts are myogenic precursor cells that are required to maintain skeletal muscle tissue. Previous studies reported that cancer-released factors deteriorate myoblast differentiation, which is one of the causes of cachexia-associated muscle wasting. We recently identified the myogenetic oligodeoxynucleotide, iSN04, which serves as an anti-nucleolin aptamer and promotes myogenesis. The present study investigated the effects of iSN04 on human myoblasts exposed to a conditioned medium (CM) of cancer cells. CM of colon cancer cell lines LoVo and HCT-116 significantly impaired myogenic differentiation and the myotube formation of human myoblasts by inducing the expression of inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor-α (TNF-α); however, the CM of the colon fibroblast cell line CCD-18Co did not. Intriguingly, iSN04 completely reversed the deterioration of myoblast differentiation by LoVo-CM by upregulating MyoD and myogenin, and downregulating myostatin, IL-1β, and TNF-α. TNF-α, of which a high level was produced in LoVo, alone inhibited myogenic differentiation and induced IL-1β, IL-6, and IL-8 transcriptions of myoblasts; however, pre-treatment with iSN04 reversed TNF-α-induced cachectic phenotypic features. The results indicate that iSN04 protects myoblasts against the effects of cancer-released factors and maintains their myogenic activity. This study provides a novel therapeutic strategy to prevent muscle loss associated with cancer cachexia.