Ninjin-yoei-to improves survival and attenuates cachexia by preserving muscle and body weight in murine models of lung cancer and fibrosis

In chronic lung diseases like lung cancer and idiopathic pulmonary fibrosis, cachexia often develops, manifesting as sustained weight decline with muscle wasting. Loss of skeletal muscle mass in a cachectic condition has been associated with breathlessness, functional limitation, and poor prognosis. Therapeutic options for cachexia have not yet been established. The traditional Japanese medicine Ninjin-yoei-to (NYT), which contains twelve crude herbal components, is applied clinically to manage loss of appetite and fatigue. We show here that NYT treatment mitigated the reductions in body weight and food intake in two different mouse models with cachexia: a bleomycin-induced lung fibrosis model and a lung adenocarcinoma model. Treatment with NYT resulted in retained muscle weights, and it suppressed the FoxO1-dependent expression of the muscle-specific ubiquitin ligases MuRF-1 and atrogin-1 in the gastrocnemius muscles of the mice, thus contributing to the maintenance of muscle contraction force and the voluntary wheel-running distance. NYT treatment also inhibited the lipolysis in white adipose tissue and suppressed the expression of uncoupling protein 1 in brown adipose tissue, leading to a reduction in energy expenditure. In the lung adenocarcinoma model, NYT treatment improved the survival rate without influencing the cancer growth. These findings suggest that NYT may serve as a therapeutic option for refractory respiratory cachexia by (i) inhibiting muscle protein degradation via the ubiquitin ligase pathway and (ii) lowering energy expenditure.