Evaluating skeletal muscle wasting and weakness in models of critical illness

Abstract

Skeletal muscle wasting and weakness are common complications associated with admission to the intensive care unit (ICU), with the loss of muscle mass and function increasing mortality and contributing to physical impairments post-discharge. While our understanding of the pathophysiology of this condition, commonly termed 'ICU-acquired weakness' (ICU-AW), has advanced considerably, no effective therapies are available. ICU-AW broadly encompasses a range of muscle-related impairments in this setting, including, but not limited to, critical illness myopathy and sepsis-induced myopathy. Pre-clinical models of critical illness can provide insights into the mechanisms underlying muscle wasting and weakness. Cell culture systems can provide mechanistic interrogation, by isolating effects to skeletal muscle directly. Small animal models, like rats and mice, allow for mechanistic investigation of ICU-AW using genetic models and testing pharmacological interventions. Larger animal models, including pigs and sheep, facilitate repeated blood and tissue sampling and can more closely recapitulate the standard-of-care within ICU settings. Although animal models can be advantageous for scientific investigation, they also have important limitations. Barriers to developing effective interventions include difficulty in obtaining muscle biopsies from patients, translating experimental findings between animal models and humans and replicating aspects of different ICU settings. This review explores the advantages and shortcomings of different pre-clinical models of critical illness, identifies gaps in understanding muscle wasting and weakness in critical illness and provides recommendations for improving the translation of therapeutics to promote functional recovery for patients post-discharge.

Keywords: animal models; cell models; critical illness; inflammation; muscle wasting; muscle weakness; sepsis; skeletal muscle.

Figure 1:. Strengths and limitations of different models of muscle wasting and weakness relevant to critical illness.

Muscle wasting and weakness with critical illness and intensive care unit (ICU) admission can be highly debilitating for patients, with significant impact on quality of life. Currently, there are no approved clinical treatments. Models of critical illness, including cell culture systems, and small and large animal models, provide experimental platforms for mechanistic interrogation and understanding how risk factors, such as age, sex and co-morbidities, contribute to an acquired myopathy. In vitro systems help isolate the effects of critical illness on skeletal muscle directly, providing excellent high-throughput screening of potential therapeutic candidates, despite lacking an integrated physiological system like in intact animal models. Small animals such as mice and rats are relatively cost-effective experimental platforms compared with larger animal models such as pigs and sheep, and their genome can be edited more easily for identifying specific genes in the conferral of protection from and/or susceptibility to wasting and weakness with critical illness. In contrast, larger animals have an immune system like that in humans with the capacity for more invasive monitoring and repeated blood and tissue sampling. *Although sheep are utilised for sepsis research, they are not commonly utilised for studying muscle wasting and weakness in critical illness. Ticks represent the disease phenotype induced in each of the different models, and crosses indicate these models are not commonly utilised for studying these conditions. Created in BioRender. Bongetti, A. (2025) https://BioRender.com/.