From bench to bedside: updates in basic science, translational and clinical research on muscle fatigue in cancer cachexia

Abstract

Purpose of review Cancer cachexia is a syndrome of loss of weight and muscle mass that leads to reduced strength, poor physical performance and functional impairment. Muscular fatigue is a distressing syndrome that patients with cachexia suffer from and can impair quality of life. Here, we review recent updates in muscular fatigue in cancer cachexia research with a focus on mechanisms, biomarkers and potential therapies. Recent findings Both in mice and humans, research has shown that muscle fatigue can be independent of muscular atrophy and can happen early in cancer development or in precachexia. Inflammatory pathways, mitochondrial dysfunction and gut microbiota have recently been studied to play an important role in muscle fatigue in preclinical models. Exercise can target these pathways and has been studied as a therapeutic intervention to improve muscle fatigue. Summary Heightened inflammation within muscle, altered muscle function and muscle fatigue can begin prior to clinical evidence of cachexia, making early recognition and intervention challenging. The emergence of cachexia mouse models and translational and clinical research studying muscle fatigue will hopefully lead to new therapies targeting the underlying mechanisms of cancer cachexia. Exercise will need to be tested in larger randomized studies before entering into daily practice.

In Vitro Models for Cancer-Associated Cachexia: The Complex Modelling of a Multiorgan Syndrome

“…Preceding the cachexia diagnosis, cancer patients often report symptoms of fatigue and muscle weakness. However, those symptoms are aggravated by the decline in muscle mass all of which can impair the patient's quality of life [19,60]. Cardiac abnormalities are often unaddressed pathological symptoms of CAC, they manifest as shortness of breath, pulmonary incapacity, and diminished exercise capacities, which are indicative of chronic heart failure [5].…”

Understanding the gut microbiota in cancer cachexia

“…Recent studies have emphasized the role of gut microbiota in both the pathogenesis and treatment of cancer, particularly as adjuvant of immunotherapy and other emerging treatments. Furthermore, investigations on gut microbiota and its involvement in changes in nutritional status among cancer patients, specifically in the context of sarcopenia and cachexia, are increasing [13 ▪ ,14].…”

Tumor cell anabolism and host tissue catabolism-energetic inefficiency during cancer cachexia

“…247–249 Kampo formulae including Hochuekkito (HET), Juzentaihoto (JTT), Ninjin’yoeito (NYT), Seishoekkito (SET), Shosaikoto (SSK), and Rikkunshito (RKT) improved appetite, anemia, protein synthesis, ghrelin levels, and reduced protein breakdown, inflammation, and adipose tissue loss in various preclinical and clinical settings of CC. 248–259…”

“…[247][248][249] Kampo formulae including Hochuekkito (HET), Juzentaihoto (JTT), Ninjin'yoeito (NYT), Seishoekkito (SET), Shosaikoto (SSK), and Rikkunshito (RKT) improved appetite, anemia, protein synthesis, ghrelin levels, and reduced protein breakdown, inflammation, and adipose tissue loss in various preclinical and clinical settings of CC. [248][249][250][251][252][253][254][255][256][257][258][259] Recently, in December 2020, Japan approved anamorelin (non-peptide ghrelin analog) for cancer cachexia treatment based on phase II trials conducted in Japanese advanced gastrointestinal and lung cancer patients, creating the hope for the development of novel drugs. 208,260,261 In addition, physical exercise has shown beneficial effects, including reduced systemic inflammation, reduced catabolism, and preserving muscle mass in CC patients along with psychological stability.…”