• breast cancer
• drug-target Mendelian randomization
• endometrial cancer
• lipid-lowering drugs

• National Natural Science Foundation of China

• Anorexia
• Lipoatrophy
• Skeletal muscle atrophy
• Treatment
• cancer cachexia

• Cachexia/metabolism
• Cachexia/etiology
• Cachexia/pathology
• Cachexia/drug therapy
• Humans
• Neoplasms/drug therapy
• Neoplasms/complications
• Neoplasms/pathology
• Neoplasms/metabolism
• Energy Metabolism/drug effects
• Animals
• Muscular Atrophy/pathology
• Muscular Atrophy/metabolism
• Muscular Atrophy/drug therapy
• Muscle, Skeletal/metabolism
• Muscle, Skeletal/pathology
• Muscle, Skeletal/drug effects
• Molecular Targeted Therapy
• Adipose Tissue/metabolism
• Adipose Tissue/pathology
• Adipose Tissue/drug effects

• Bovine mammary epithelial cells
• CLA
• HIF-1α
• LiCl
• SREBP1
• β-catenin

• Humans
• Animals
• Cattle
• Lithium Chloride/pharmacology
• Lithium Chloride/analysis
• Lithium Chloride/metabolism
• beta Catenin/metabolism
• Linoleic Acids, Conjugated/analysis
• Linoleic Acids, Conjugated/metabolism
• Linoleic Acids, Conjugated/pharmacology
• Glycogen Synthase Kinase 3 beta/analysis
• Glycogen Synthase Kinase 3 beta/metabolism
• Glycogen Synthase Kinase 3 beta/pharmacology
• Mammary Glands, Animal/metabolism
• Milk/chemistry
• Stearoyl-CoA Desaturase
• Epithelial Cells/metabolism
• Fatty Acids/metabolism

• Bovine mammary epithelial cell
• Hypoxia-inducible factor 1α
• Lithium chloride
• β-Catenin

• Female
• Cattle
• Animals
• Milk Proteins/metabolism
• Lithium Chloride/pharmacology
• Lithium Chloride/metabolism
• STAT5 Transcription Factor/genetics
• STAT5 Transcription Factor/metabolism
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• beta Catenin/metabolism
• Signal Transduction
• RNA, Messenger/metabolism
• Mammary Glands, Animal/metabolism
• Epithelial Cells/metabolism

• cancer
• exercise
• immunity
• inflammation
• metabolism
• physical activity
• training

• Cancer cachexia
• Cardiac function
• Muscle wasting
• Survival
• Tissue-protective molecule

• PGC-1α
• cancer cachexia
• metabolism
• mitochondria
• muscle wasting
• myogenesis
• regeneration

Muscle wasting, i.e., cachexia, frequently occurs in cancer and associates with poor prognosis and increased morbidity and mortality. Anticancer treatments have also been shown to contribute to sustainment or exacerbation of cachexia, thus affecting quality of life and overall survival in cancer patients. Pre-clinical studies have shown that blocking activin receptor type 2 (ACVR2) or its ligands and their downstream signaling can preserve muscle mass in rodents bearing experimental cancers, as well as in chemotherapy-treated animals. In tumor-bearing mice, the prevention of skeletal and respiratory muscle wasting was also associated with improved survival. However, the definitive proof that improved survival directly results from muscle preservation following blockade of ACVR2 signaling is still lacking, especially considering that concurrent beneficial effects in organs other than skeletal muscle have also been described in the presence of cancer or following chemotherapy treatments paired with counteraction of ACVR2 signaling. Hence, here, we aim to provide an up-to-date literature review on the multifaceted anti-cachectic effects of ACVR2 blockade in preclinical models of cancer, as well as in combination with anticancer treatments.

• activins
• cancer cachexia
• chemotherapy
• mortality
• multi-organ
• muscle wasting
• myostatin
• survival
• tumor

• muscle cachexia
• pSTAT3 inhibitors
• targeted therapy

Cancer cachexia (CC) is a multifactorial syndrome characterized by systemic inflammation, uncontrolled weight loss and dramatic metabolic alterations. This includes myofibrillar protein breakdown, increased lipolysis, insulin resistance, elevated energy expediture, and reduced food intake, hence impairing the patient's response to anti-cancer therapies and quality of life. While a decade ago the syndrome was considered incurable, over the most recent years much efforts have been put into the study of such disease, leading to the development of potential therapeutic strategies. Several important improvements have been reached in the management of CC from both the diagnostic-prognostic and the pharmacological viewpoint. However, given the heterogeneity of the disease, it is impossible to rely only on single variables to properly treat patients presenting this metabolic syndrome. Moreover, the cachexia symptoms are strictly dependent on the type of tumor, stage and the specific patient's response to cancer therapy. Thus, the attempt to translate experimentally effective therapies into the clinical practice results in a great challenge. For this reason, it is of crucial importance to further improve our understanding on the interplay of molecular mechanisms implicated in the onset and progression of CC, giving the opportunity to develop new effective, safe pharmacological treatments. In this review we outline the recent knowledge regarding cachexia mediators and pathways involved in skeletal muscle (SM) and adipose tissue (AT) loss, mainly from the experimental cachexia standpoint, then retracing the unimodal treatment options that have been developed to the present day.

• animal models
• cachexia mediators
• cancer cachexia
• clinical trials
• muscle tissue and adipose tissue loss
• therapeutic strategies

• Activin
• Acute phase response
• MDSC
• Myostatin
• Physical activity
• Protein synthesis

Erythropoietin (Epo) exerts direct effects on white adipose tissue (WAT) in mice in addition to its erythropoietic effects, and in humans Epo increases resting energy expenditure and affect serum lipid levels, but direct effects of Epo in human WAT have not been documented. We therefore investigated the effects of acute and prolonged Epo exposure on human WAT in vivo.

Data were obtained from two clinical trials: 1) acute Epo exposure (rHuEpo, 400 IU/kg) followed by WAT biopsies after 1 h and 2) 10 weeks treatment with the erythropoiesis-stimulating agent (ESA) Darbepoietin-alpha. Biopsies were analyzed by PCR for Epo receptor (Epo-R) mRNA. A new and highly specific antibody (A82, Amgen) was used to evaluate the presence of Epo-R by western blot analysis in addition to Epo-R signaling proteins (Akt, STAT5, p70s6k, LYN, and p38MAPK), activation of lipolytic pathways (ATGL, HSL, CGI-58, G0S2, Perilipin, Cidea, Cidec, AMPK, and ACC), and mitochondrial biogenesis (VDAC, HSP90, PDH, and SDHA).

No evidence of in vivo activation of the Epo-R in WAT could be documented despite detectable levels of Epo-R mRNA.

Thus, in contradiction to animal studies, Epo treatment within a physiological relevant range in humans does not exert direct effects in a subcutaneous WAT.

• Darbepoietin-α
• Lipolysis
• Mitochondria
• rHuEpo

• PGC-1α
• Pathology Section
• cancer cachexia
• erythropoietin
• exercise training
• mitochondria

• Anemia/drug therapy
• Anemia/etiology
• Animals
• Blotting, Western
• Cachexia/etiology
• Cachexia/prevention & control
• Disease Models, Animal
• Epoetin Alfa/pharmacology
• Exercise Therapy/methods
• Female
• Hematinics/pharmacology
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Transgenic
• Microscopy, Electron, Transmission
• Muscle, Skeletal/drug effects
• Muscle, Skeletal/pathology
• Muscular Atrophy/etiology
• Muscular Atrophy/prevention & control
• Neoplasms, Experimental/complications
• Physical Conditioning, Animal
• Real-Time Polymerase Chain Reaction

• Cancer cachexia
• Pharmacological treatment
• Physical exercise

• R01 CA160688 NCI NIH HHS
• T32 CA085159 NCI NIH HHS

Bufei Jianpi granules has been confirmed effective in improving pulmonary function, alleviating acute exacerbations, improving six-minute walk distance and quality of life, and benefited in 12-month follow-up in chronic obstructive pulmonary disease (COPD) patients with syndrome of lung-spleen qi deficiency. Skeletal muscle dysfunction (SMD), an important extrapulmonary complication, occurs in the very initiation of COPD and is closely related to morbidity and mortality. To evaluate the efficacy of Bufei Jianpi granules on SMD, we observed skeletal muscular function and histomorphology, mitochondrial morphormetry and proteins in COPD rats induced by cigarette-smoke and Klebsiella pneumoniae.

Seventy-two Sprague–Dawley rats were randomized into Control + Saline, Control + Bufei Jianpi, Control + Aminophylline, COPD + Saline, COPD + Bufei Jianpi and COPD + Aminophylline groups. From week 9 to 20, rats were administrated intragastricly by normal saline, Bufei Jianpi granules and aminophylline, respectively. Muscular tension and fatigue index of intercostal muscle, quadriceps, biceps and soleus were detected by using electrophysiological technology. Pathological and ultrastructural changes and expressions of mitochondrial Bcl-2 nineteen-kilodalton interacting protein 3 (Bnip3) and cytoplasm cytochrome C (Cyto C) in the four skeletal muscles were observed by using optical and electron microscope and western blotting.

There was no statistical difference among the control rats treated with saline, Bufei Jianpi granules or aminophylline in above-mentioned parameters. Muscular tension, mitochondria volume density (Vv) and compared membrane surface (δm) of the four muscles were significantly lower in COPD + Saline group compared to Control + Saline group, while fatigue index, mitochondria surface area (δ), Bnip3 and Cyto C were higher (P < 0.05). COPD rats showed more morphological changes in muscle tissues than controls, such as atrophy, degeneration, necrosis and matrix hyperplasia. Utrastructurally, mitochondria populations decreased significantly in the four muscles, and were shrunken and even cavitation changed. The up-mentioned parameters were improved in Bufei Jianpi group (P < 0.05) in the four muscles.

Bufei Jianpi granules can improve skeletal muscle function via improving mitochondria population and function, reducing apoptotic factors such as Bnip3 and Cyto C, and is more effective than aminophylline.

• muscle wasting
• ubiquitin ligases
• autophagy
• muscle regeneration

Erythropoietin (EPO), the required cytokine for promoting the proliferation and differentiation of erythroid cells to stimulate erythropoiesis, has been reported to act as a pleiotropic cytokine beyond hematopoietic system. The various activities of EPO are determined by the widespread distribution of its cell surface EPO receptor (EpoR) in multiple tissues including endothelial, neural, myoblasts, adipocytes and other cell types. EPO activity has been linked to angiogenesis, neuroprotection, cardioprotection, stress protection, anti-inflammation and especially the energy metabolism regulation that is recently revealed. The investigations of EPO activity in animals and the expression analysis of EpoR provide more insights on the potential of EPO in regulating energy metabolism and homeostasis. The findings of crosstalk between EPO and some important energy sensors and the regulation of EPO in the cellular respiration and mitochondrial function further provide molecular mechanisms for EPO activity in metabolic activity regulation. In this review, we will summarize the roles of EPO in energy metabolism regulation and the activity of EPO in tissues that are tightly associated with energy metabolism. We will also discuss the effects of EPO in regulating oxidative metabolism and mitochondrial function, the interactions between EPO and important energy regulation factors, and the protective role of EPO from stresses that are related to metabolism, providing a brief overview of previously less appreciated EPO biological function in energy metabolism and homeostasis.

• Erythropoietin
• erythroid system
• pleiotropic cytokine