Abstract
Simple SummaryMuscle wasting is a symptom of the cancer cachexia closely related to the imbalance between protein synthesis and degradation. MyomiRs are small RNA molecules that do not encode proteins and have the function of regulating protein-coding genes, and in this way, myomiRs can regulate the homeostasis of skeletal muscle cells submitted to physiological or pathological stimulus. Aerobic exercise training (AET) is a nonpharmacological adjuvant treatment to prevent cancer cachexia, improving the patient’s quality of life. MyomiRs are modulated by cancer and AET, as well. Thus, we propose to investigate the effects promoted by AET on circulating and skeletal muscle myomiRs in cachectic and non-cachectic cancer mice. Exercise is a promising therapy for cancer-associated muscle wasting, revealing the importance to understand the molecular mechanisms involved to preserve muscle mass.We investigated the effects of AET on myomiRs expression in the skeletal muscle and serum of colon cachectic (CT26) and breast non-cachectic (MMTV-PyMT) cancer mice models. Colon cancer decreased microRNA-486 expression, increasing PTEN in tibialis anterior muscle (TA), decreasing the PI3K/mTOR protein pathway, body and muscle wasting, fibers’ cross-sectional area and muscle dysfunction, that were not preserved by AET. In contrast, breast cancer decreased those muscle functions, but were preserved by AET. In circulation, the downregulation of microRNA-486 and -206 in colon cancer, and the downregulation of microRNA-486 and upregulation of microRNA-206 expression in breast cancer might be good cancer serum biomarkers. Since the microRNA-206 is skeletal muscle specific, their expression was increased in the TA, serum and tumor in MMTV, suggesting a communication among these three compartments. The AET prevents these effects on microRNA-206, but not on microRNA-486 in MMTV. In conclusion, cancer induced a downregulation of microRNA-486 expression in TA and serum of CT26 and MMTV mice and these effects were not prevented by AET; however, to MMTV, the trained muscle function was preserved, probably sustained by the downregulation of microRNA-206 expression. Serum microRNA-206 is a potential biomarker for colon (decreased) and breast (increased) cancer to monitor the disease evolution and the effects promoted by the AET.
Highlights
IntroductionCancer cachexia is characterized by the progressive loss of lean body mass, with or without the loss of adipose tissue that can be partially but not totally reversed by diet support [1], and the skeletal muscle is the main tissue of protein loss [2]
Cachexia is a syndrome associated with several neoplastic diseases
The results showed no significant change in exercise capacity throughout the study in the wild type sedentary (WT) group PRE-Aerobic exercise training (AET) (618.9 m ± 47.8) within groups 619.2 m ± 156.6 vs. 618.9 m ± 47.8 vs. 640.1 m ± 75.4, p > 0.05 (Figure 1B)
Summary
Cancer cachexia is characterized by the progressive loss of lean body mass, with or without the loss of adipose tissue that can be partially but not totally reversed by diet support [1], and the skeletal muscle is the main tissue of protein loss [2]. One of the main manifestations of the damage that neoplastic diseases cause, causes muscle atrophy, which is the result of an imbalance between protein synthesis and degradation in skeletal muscle [3]. The reasons for cancer-reduced skeletal muscle mass, cellular mechanism and function are still poorly understood. One of the possible mechanisms is through an altered expression of microRNAs in skeletal muscle [4]. MyomiRs are a set of microRNAs exclusively expressed in skeletal and cardiac muscle, that have been identified as physiological regulators of myogenesis, muscle fiber-type composition, muscle growth and cellular homeostasis [6]. MyomiRs influence myogenesis and muscle damage repair preventing skeletal muscle injuries and dysfunction [7]
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