Exogenous insulin‐like growth factor 1 attenuates cisplatin‐induced muscle atrophy in mice

Abstract

Background A reduction in the skeletal muscle mass worsens the prognosis of patients with various cancers. Our previous studies indicated that cisplatin administration to mice caused muscle atrophy. This is a concern for human patients receiving cisplatin. The insulin-like growth factor 1 (IGF-1)/phosphoinositide 3-kinase (PI3K)/Akt pathway stimulates the rate of protein synthesis in skeletal muscle. Thus, IGF-I can be a central therapeutic target for preventing the loss of skeletal muscle mass in muscle atrophy, although it remains unclear whether pharmacological activation of the IGF-1/PI3K/Akt pathway attenuates muscle atrophy induced by cisplatin. In this study, we examined whether exogenous recombinant human IGF-1 attenuated cisplatin-induced muscle atrophy. Methods Male C57BL/6J mice (8-9 weeks old) were injected with cisplatin or saline for four consecutive days. On Day 5, quadriceps muscles were isolated. Mecasermin (recombinant human IGF-1) or the vehicle control was subcutaneously administered 30 min prior to cisplatin administration. A dietary restriction group achieving weight loss equivalent to that caused by cisplatin administration was used as a second control. C2C12 myotubes were treated with cisplatin with/without recombinant mouse IGF-1. The skeletal muscle protein synthesis/degradation pathway was analysed by histological and biochemical methods. Results Cisplatin reduced protein level of IGF-1 by about 85% compared with the vehicle group and also reduced IGF-1/PI3K/Akt signalling in skeletal muscle. Under this condition, the protein levels of muscle ring finger protein 1 (MuRF1) and atrophy gene 1 (atrogin-1) were increased in quadriceps muscles (MuRF1; 3.0 ± 0.1 folds, atrogin-1; 3.0 ± 0.3 folds, P < 0.001, respectively). The administration of a combination of cisplatin and IGF-1 significantly suppressed the cisplatin-induced downregulation of IGF-1/PI3K/Akt signalling and upregulation of MuRF1 and atrogin-1 (up to 1.6 ± 0.3 and 1.5 ± 0.4 folds, P < 0.001, respectively), resulting in diminished muscular atrophy. IGF-1 showed similar effects in cisplatin-treated C2C12 myotubes, as well as the quadriceps muscle in mice. Conclusions The downregulation of IGF-1 expression in skeletal muscle might be one of the factors playing an important role in the development of cisplatin-induced muscular atrophy. Compensating for this downregulation with exogenous IGF-1 suggests that it could be a therapeutic target for limiting the loss of skeletal muscle mass in cisplatin-induced muscle atrophy.

Prevalence of sarcopenia in patients with solid tumors: A meta‐analysis based on 81,814 patients

“…Furthermore, other cytokines, such as myostatin, activin, and transforming growth factor‐beta are significantly increased in cancers and trigger the degradation of muscle myofibrillar protein 22 . Also, chemotherapeutic agents, such as cisplatin can induce damage of the skeletal musculature 24 . Finally, most tumor patients are older and cancer‐related LSMM/sarcopenia develops in patients with already‐existing age‐related sarcopenia.…”

“…22 Also, chemotherapeutic agents, such as cisplatin can induce damage of the skeletal musculature. 24 Finally, most tumor patients are older and cancer-related LSMM/sarcopenia develops in patients with already-existing age-related sarcopenia.…”

Cardiomyocyte Atrophy, an Underestimated Contributor in Doxorubicin-Induced Cardiotoxicity

“…Studies have uncovered that IGF-1 is a pro-hypertrophic inducer in cardiomyocyte (84,85). Further, exogenous IGF-1 reversed cisplatin-induced skeleton muscle atrophy through inhibiting PI3K-AKT-FOXO mediated UPS (86). Overexpression of IGF-1 was also found to ameliorate cardiac atrophy in spinal muscular atrophy mice (87).…”

Commentary: Association of Sarcopenia with Toxicity and Survival in Postoperative Recurrent Esophageal Squamous Cell Carcinoma Patients Receiving Chemoradiotherapy

“…As an example, primary and secondary hypogonadism is seen as a complication in male cancer patients and is a well-known triggering factor for loss of muscle strength ( 12 ). The downregulation of IGF-1 expression in skeletal muscle might also be one of the factors playing an important role in the development of muscular atrophy in cancer patients, such as in those treated with chemotherapy ( 13 ). These strength-related hormonal factors, i.e., testosterone ( 14 ) and insulin-like growth factor-I ( 15 , 16 ), which decline with the presence of cancer and muscle strength, might explain why strength appears to be such a powerful marker of risk.…”