JCSM rapid communications最新文献

Background: Low muscle in cancer is associated with an increase in treatment-related toxicities and is a predictor of cancer-related and all-cause mortality. The mechanisms of cancer-related muscle loss are multifactorial, including anorexia, hypogonadism, anaemia, inflammation, malnutrition, and aberrations in skeletal muscle protein turnover and metabolism.

Methods: In this narrative review, we summarise relevant literature to (i) review the factors influencing skeletal muscle mass regulation, (ii) provide an overview of how cancer/treatments negatively impact these, (iii) review factors beyond muscle signalling that can impact the ability to participate in and respond to an exercise intervention to counteract muscle loss in cancer, and (iv) provide perspectives on critical areas of future research.

Results: Despite the well-known benefits of exercise, there remains a paucity of clinical evidence supporting the impact of exercise in cancer-related muscle loss. There are numerous challenges to reversing muscle loss with exercise in clinical cancer settings, ranging from the impact of cancer/treatments on the molecular regulation of muscle mass, to clinical challenges in responsiveness to an exercise intervention. For example, tumour-related/treatment-related factors (e.g. nausea, pain, anaemia, and neutropenia), presence of comorbidities (e.g. diabetes, arthritis, and chronic obstructive pulmonary disease), injuries, disease progression and bone metastases, concomitant medications (e.g., metformin), can negatively affect an individual's ability to exercise safely and limit subsequent adaptation.

Conclusions: This review identifies numerous gaps and oppportunities in the area of low muscle and muscle loss in cancer. Collaborative efforts between preclinical and clinical researchers are imperative to both understanding the mechanisms of atrophy, and develop appropriate therapeutic interventions.

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Rehabilitating cachexia: development and functional characterization of a novel longitudinal and translational model of cancer-associated cachexia

Ishan Roy^1,2, Ben Binder-Markey^1,2, Danielle Sychowski¹, Donna McAllister³, Dominic D'Andrea¹, Colin Franz^1,2, Michael B. Dwinell³ and Richard L. Lieber^1,2

¹Shirley Ryan AbilityLab (formerly known as Rehabilitation Institute of Chicago), Chicago, IL, USA; ²Department of Physical Medicine and Rehabilitation, Northwestern University, Chicago, IL, USA; ³Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, WI, USA

Introduction: The physiologic mechanisms that drive functional changes due to cachexia are poorly understood. Existing cachexia models limit our ability to address these mechanisms because they either express a rare tumour type or cause rapid death. Such models are not amenable to multi-domain functional analysis of rehabilitation protocols, which typically require 6–8 weeks. The goal of this study was to develop and functionally characterize a longitudinal model of cancer-associated cachexia.

Methods: The “KPC orthotopic injection” pancreatic cancer mouse model was selected for optimization. We tested multiple cell clones, cell doses, and vehicle types in order to maximize survival. Ex vivo analysis included skeletal and cardiac muscle mass. Functional characterization included: hind-limb grip strength for muscle function; open-field arena for ambulation and anxiety; Y-maze for spatial memory; and Morris Water Maze and Rotarod for endurance.

Results: Serial dilution of multiple KPC clones yielded optimal conditions for extending median survival, from 3 weeks up to 8.5 weeks post-injection using the KPC orthotopic model (p < 0.0001). In weekly ex vivo analysis, the optimized model resulted in progressive skeletal and cardiac muscle mass loss at 5 weeks post-injection and continued through 9 weeks (p < 0.01). Starting 5 weeks post-injection, animals had 8% decline in grip strength (p < 0.01) and a sustained decrease in distance ambulated and gait speed of 30–50% (p < 0.05). Animal subjects retained spatial memory similar to controls, indicating that functional deficits were not confounded by behavioural change. There was also a trend towards decreased motor endurance (p = 0.07) at 5 weeks and increased open-field anxiety (p = 0.06) at 8 weeks.

Conclusion: This optimized model of cancer-associated cachexia demonstrates progressive loss of muscle and function in multiple domains while accounting for potential confounding factors of cognition and behaviour. The model is tailored for longitudinal studies and sets the stage for mechanistic and translational studies o