Abstract
Cancer chemotherapy induces sarcopenia, which is a rapid loss of muscle mass that directly restricts daily activities and leads to poor quality of life and increased mortality. Although hormone-related therapies have been used to improve appetite and nutritional status, current treatments are considered palliative. Thus, the protection of skeletal muscle loss without adverse effects is essential to allow the maintenance of chemotherapy in cancer patients. Magnolol from Magnolia officinalis has several pharmacological effects including anti-cancer and anti-inflammatory activities, but the protection from muscle atrophy is not well-understood. In the present study, we investigated the effects of magnolol on muscle wasting and macrophage subtypes in a cisplatin-induced sarcopenia mouse model. We showed that magnolol significantly attenuated the body weight and the muscle loss induced by cisplatin injection. The diameter of the tibialis anterior muscle was markedly increased after magnolol treatment in cisplatin-treated mice. Importantly, magnolol increased macrophage infiltration into skeletal muscle while not affecting proliferation of macrophages. Magnolol attenuated the imbalance of M1/M2c macrophages by increasing CD206+CD163+ M2c tissue reparative macrophages. Further, magnolol increased insulin-like growth factor (IGF)-1 expression. This effect was also observed in bone marrow-derived macrophages upon magnolol treatment. Taken together, magnolol may be a promising chemoprotective agent for the prevention of muscle atrophy through the upregulating M2c macrophages, which are a major source of IGF-1.
Highlights
Sarcopenia, a pivotal feature of cancer cachexia, is defined as degenerative skeletal muscle loss and decline of muscle strength [1]
Our findings showed that magnolol treatment increased the infiltration of macrophages into muscle tissue
We further showed that increase of CD163+ M2c macrophages and insulin-like growth factor (IGF)-1 expression by magnolol treatment attenuated the muscle atrophy in mice
Summary
Sarcopenia, a pivotal feature of cancer cachexia, is defined as degenerative skeletal muscle loss and decline of muscle strength [1]. Chemotherapies trigger nuclear factor kappaB (NF-κB) activation [3, 4], which directly increases proteolysis and the release of inflammatory mediators in early phase [5, 6]. The tissue microenvironment becomes rich with inflammatory signals from activated immune cells. Macrophages in muscles play a central role in the activation and protection of myofibers after muscle inflammation and injury [7]. Alternatively activated M2 macrophages at the injury site are more abundant during the late phase of tissue repair. M2c macrophages defined as CD163-expressing macrophages sustain muscle healing and are regarded as an important source of insulin-like growth factor (IGF)-1, which mediates muscle cell proliferation, differentiation, and the survival [15, 16]. M1 and M2 macrophage balance is critical in muscle protection [15, 17]
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