Objective To investigate the effects of aerobic exercise and different exercise habits on skeletal muscle function and the possible molecular mechanisms in colorectal cancer-loaded mice. Methods Thirty-five 5-week-old BABL / c male mice were acclimatized to feeding for 1 week and then divided randomly into the following groups: control (D), tumor (M), exercise preconditioning (QAM), lifetime exercise (AM), and exercise (HAM) groups (n = 7 mice per group). Mice in the QAM and AM groups underwent aerobic exercise regimen 1 from weeks2 ~ 6. At week 7, mice in the experimental groups received 0. 2 mL of CT26 colon cancer cell suspension subcutaneously in the dorsal aspect of the left hind limb, while control mice received 0. 2 mL of saline at the corresponding site. Mice in the AM and HAM groups were subjected to aerobic exercise regimen 2 for weeks 7 ~ 9.The general status and skeletal muscle mass and function were monitored in all mice throughout the experiments. After completion of the experiment, samples were collected and the cross-sectional area of gastrocnemius muscle fibers (CSA) was measured by hematoxylin and eosin staining and expression levels of proteins related to synthesis and catabolism of the gastrocnemius muscle were analyzed by Western Blot. Results ( 1) The weight ratio of the gastrocnemius muscle was significantly lower in mice in the M, QAM, and HAM groups compared with group D, and was significantly higher in AM mice compared with M, QAM, and HAM mice. (2)Grip strength, endurance, skeletal muscle circumference, and CSA were significantly lower in group D mice compared with the other groups, and was most enhanced in group HAM. Endurance and CSA were consistently enhanced in groups QAM, AM, and HAM. (3)Muscle RING-finger protein-1 (MuRF1) expression levels were significantly lower in groups M, QAM, AM, and HAM than in group D, significantly lower in groups AM and HAM than in group M, and significantly lower in group HAM than in group QAM. (4) Fibronectin type Ⅲ domain-containing protein 5 ( FNDC5) expression levels were significantly lower in group M than in groups D and QAM. ( 5) Peroxisome proliferator-activated receptor gamma coactivator 1-alpha expression levels were significantly lower in the QAM and HAM groups compared with group M.(6)Expression levels of phospho (p)-AMP-activated protein kinase (AMPK) / AMPK and p-AMPK were significantly higher in group QAM than in groups D and M, p-AMPK expression significantly lower in groups AM and HAM was than in group QAM, and AMPK expression was significantly lower in groups QAM, AM, and HAM than in group D. Conclusions Exercise preconditioning and continuous aerobic exercise can improve skeletal muscle mass and function in CT26 colon cancer-loaded mice by activating AMPK phosphorylation to stimulate skeletal muscle secretion of FNDC5, thereby regulating the expression of MuRF1 protein.