Accumulating evidence shows that microRNAs, functioning as either oncogenes or tumour suppressors by negatively regulating downstream target genes that are actively involved in tumour initiation and progression, may be promising biomarkers and therapy targets. Data mining through a microRNA chip database indicated that let-7c may be associated with tumour metastasis. Here, we confirmed that down-regulation of let-7c in primary cancer tissues was significantly associated with metastases, advanced TNM stages and poor survival of colorectal cancer patients. Moreover, ectopic expression of let-7c in a highly metastatic Lovo cell line remarkably suppressed cell migration and invasion in vitro by the down-regulation of K-RAS, MMP11 and PBX3, as well as tumour growth and metastases in vivo, whereas inhibition of let-7c in low-metastatic HT29 cells increased cell motility and invasion by the enhanced gene expression of K-RAS, MMP11 and PBX3. Interestingly, the luciferase reporters' activities with the 3'-UTRs of K-RAS, MMP11 and PBX3 were inhibited significantly by let-7c. Importantly, rescue experiments involving the over-expression of these genes without their 3'-UTRs completely reversed the effects of let-7c on tumour metastasis, both in vitro and in vivo. Finally, the levels of let-7c were inversely correlated with those of MMP11 and PBX3, but not with those of K-RAS. Taken together, these results demonstrate that let-7c, apart from its tumour growth suppression role, also functions as a tumour metastasis suppressor in colorectal cancer by directly destabilizing the mRNAs of MMP11 and PBX3 at least.
Background Age-associated sarcopenia is characterized of progressed loss of skeletal muscle power, mass, and function, which affects human physical activity and life quality. Besides, accompanied with sarcopenia, aged population also faces a series of metabolic dysfunctions. Irisin, the cleaved form of fibronectin type III domain-containing protein 5 (FNDC5), is a myokine induced by exercise and has been shown to exert multiple beneficial effects on health. The goal of the study is to investigate the alterations of Fndc5/irisin in skeletal muscles during ageing and whether irisin administration could ameliorate age-associated sarcopenia and metabolic dysfunction. Methods The mRNA and protein levels of FNDC5/irisin in skeletal muscle and serum from 2-and 24-month-old mice or human subjects were analysed using qRT-PCR and western blot. FNDC5/irisin knockout mice were generated to investigate the consequences of FNDC5/irisin deletion on skeletal muscle mass, as well as morphological and molecular changes in muscle during ageing via histological and molecular analysis. To identify the therapeutic effects of chronic irisin treatment in mice during ageing, in vivo intraperitoneal administration of 2 mg/kg recombinant irisin was performed three times per week in ageing mice (14-month-old) for 4 months or in aged mice (22-month-old) for 1 month to systematically investigate irisin's effects on age-associated sarcopenia and metabolic performances, including grip strength, body weights, body composition, insulin sensitivity, energy expenditure, serum parameters and phenotypical and molecular changes in fat and liver. Results We showed that the expression levels of irisin, as well as its precursor Fndc5, were reduced at mRNA and protein expression levels in muscle during ageing. In addition, via phenotypic analysis of FNDC5/irisin knockout mice, we found that FNDC5/irisin deficiency in aged mice exhibited aggravated muscle atrophy including smaller grip strength (À3.23%, P < 0.05), muscle weights (quadriceps femoris [QU]: À20.05%; gastrocnemius [GAS]: À17.91%; tibialis anterior [TA]: À19.51%, all P < 0.05), fibre size (QU: P < 0.01) and worse molecular phenotypes compared with wild-type mice. We then delivered recombinant irisin protein intraperitoneally into ageing or aged mice and found that it could improve sarcopenia with grip strength (+18.42%, P < 0.01 or +13.88%, P < 0.01), muscle weights (QU: +9.02%, P < 0.01 or +16.39%, P < 0.05), fibre size (QU: both P < 0.05) and molecular phenotypes and alleviated age-associated fat tissues expansion, insulin resistance and hepatic steatosis (all P < 0.05), accompanied with altered gene signatures. Conclusions Together, this study revealed the importance of irisin in the maintenance of muscle physiology and systematic energy homeostasis during ageing and suggested a potent therapeutic strategy against age-associated metabolic diseases via irisin administration.
INTRODUCTION An increase in life expectancy in modern world brings an 'aged society', in which a substantial aging population poses challenges both medically and financially [1, 2]. Thus, more and more research interests are piqued toward the combat against aging. Generally, aging is defined as the age-dependent physiological decline that affects all living organisms. Aging undermines multiple major organs and plays a profound role in the onset of neurodegenerative diseases, cardiovascular diseases, metabolic disorders, as well as a loss in muscle and bone mass [3-7]. Recently, metabolic fitness emerges as a novel player in the arena of combating aging. For instance, the prevalence www.aging-us.com
Sarcopenia is characterized of muscle mass loss and functional decline in elder individuals which severely affects human physical activity, metabolic homeostasis, and life quality. Physical exercise is considered effective in combating muscle atrophy and sarcopenia, yet it is not feasible to elders with limited mobility. PGC‐1α4, a short isoform of PGC‐1α, is strongly induced in muscle under resistance training, and promotes muscle hypertrophy. In the present study, we showed that the transcriptional levels and nuclear localization of PGC1α4 was reduced during aging, accompanied with muscle dystrophic morphology, and gene programs. We thus designed NLS‐PGC1α4 and ectopically express it in myotubes to enhance PGC1α4 levels and maintain its location in nucleus. Indeed, NLS‐PGC1α4 overexpression increased muscle sizes in myotubes. In addition, by utilizing AAV‐NLS‐PGC1α4 delivery into gastrocnemius muscle, we found that it could improve sarcopenia with grip strength, muscle weights, fiber size and molecular phenotypes, and alleviate age‐associated adiposity, insulin resistance and hepatic steatosis, accompanied with altered gene signatures. Mechanistically, we demonstrated that NLS‐PGC‐1α4 improved insulin signaling and enhanced glucose uptake in skeletal muscle. Besides, via RNA‐seq analysis, we identified myokines IGF1 and METRNL as potential targets of NLS‐PGC‐1α4 that possibly mediate the improvement of muscle and adipose tissue functionality and systemic energy metabolism in aged mice. Moreover, we found a negative correlation between PGC1α4 and age in human skeletal muscle. Together, our results revealed that NLS‐PGC1α4 overexpression improves muscle physiology and systematic energy homeostasis during aging and suggested it as a potent therapeutic strategy against sarcopenia and aging‐associated metabolic diseases.
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