Future Directions in Critical Care Research: Autophagy and Muscle Hacking

One of the many facets of critical illness is myopathy, which is associated with increased morbidity and mortality. Here, we delve into the metabolic drivers of muscle wasting, its overlap with frailty syndromes, and how insights into the pathways involved may unveil potential therapeutic strategies.

Critical care reflects gruelling illness. Medium to long-term outcomes also reflect a degradation in quality of life, by multiple measures. For example, patients report disruption to sleep, mood, exercise tolerance, levels of independence, loss or reduced employment, increased care burden and experience higher rates of hospital admission and health limitations than non-ICU controls (Hill et al. 2016). Muscle loss is marked and seriously impairs patients' respiratory wean in addition to ongoing rehabilitation, in turn affecting what their optimal functional outcomes could be.

Historically and culturally, the metabolic failure component of critical illness has been omitted from trials and general interest areas, because it is complicated and realistically difficult to find targeted therapies for. Enteral nutrition, the most studied intervention, has witnessed repeated rounds of failure to improve muscle strength despite increased protein supplementation (Bels et al. 2024).

This is a meander through mechanisms for muscle loss in critical illness, the evolutionary purpose of skeletal muscle sacrifice, and what strategies or screening criteria we can consider when prognosticating what survival from critical illness looks like for patients and their families. There is also now a wide range of potential therapies that we can borrow from sister specialties to offset some of these changes.

What is Autophagy?

Autophagy is a key cellular pathway that recycles cell components to maintain rigorous quality control. The pathway transports cytoplasmic waste or unwanted products to a lysosome for degradation. The most researched form of autophagy is macroautophagy, where a double-membraned structure expands and encloses cytosolic components within an autophagosome. This vesicle merges with a lysosome to become an autolysosome (Bels et al. 2024). Within the autolysosome, proteolytic, lipolytic and glycolytic enzymes divide the sequestered content, allowing the cell to recycle the resulting breakdown products. 

Autophagy is finely regulated by a complex system of regulatory mediators and signalling pathways (Fazzini et al. 2023). Human cells have tonic autophagy activity, which is upregulated at times of cellular stress such as insufficient energy, deficient nutrient stores, or following accumulation of waste products. 

Beyond its role in large-scale waste product removal, autophagy can selectively target misfolded proteins such as those associated with Alzheimer's disease. It is also vital for preventing time and inflammation-associated damage to tempestuous cell structures such as mitochondria, from which free oxygen radical leak is an ever-present threat.

Successful autophagy is necessary to prevent ageing – failure of this mechanism occurs in chronic illness and frailty. It is also requisite for repairing organs after illness – the bridge between life/organ support, and recovery. It may also represent a ‘biohack’ method of protecting or regenerating muscle after critical illness – the holy grail of critical care.

IL-6 Pathway

How is muscle lost in critical illness

There are multiple pathways through which muscle is lost during inflammation/infection/illness. Two notable pathways include the IL-6 cytokine pathway and the kynurenine pathway. IL-6 is a sentinel cytokine that, in small doses, is released in exercise and can contribute to muscle growth and integrity. However, in the thresholds reached in chronic and acute illness, there are multiple central and peripheral routes by which IL-6 is pathological. Drugs that inhibit this molecule are protective against sarcopenia (Hill et al. 2016).

Kyurenine Pathway

The Kyurenine pathway represents the biological pathway by which 95% of tryptophan, the amino acid, is degraded. The pathway has recently been identified as significant for immune function and muscle atrophy. Tryptophan is significant because it contains a moiety called an indole ring, with niche biological activity. An enzyme called IDO-1 helps regulate this breakdown. A notable number of cell types are dependent on tryptophan as a metabolic substrate for such reasons – T cells being an excellent example (Stone and Williams 2023). Their proliferation is heavily affected by tryptophan availability. Thus, there is a direct amino acid sacrifice to favour a T cell immune response. In addition, the common endpoint of the kyurenine pathway is  NAD+, which feeds directly into the TCA cycle and perturbs mitochondrial activity. Moreover, it modifies DNA expression via the action of sirtuins – this can broadly set cells into a 'feast or famine' state where they grow or repair accordingly.

Why is Skeletal Muscle Sacrificed in Critical Illness?

It is important to remember that muscle is a dynamic living tissue with metabolic roles in addition to biomechanical ones. Locomotion is not a priority in severe illness – be it predator-prey identification, or sedate sickness behaviour; most organisms will slow or still under significant biological stress. It is emerging that beyond the obvious cardiovascular benefits of muscle mass and exercise, immunometabolic roles exist; affected by ageing, frailty and chronic inflammation. Sarcopenia is a direct symptom of frailty and can be considered ‘muscle failure’ in all its forms, just as heart or renal failure impacts overall physical function.

Muscle is deliberately lost in an acute stress response – and we know this from repeated studies identifying wasting of quadriceps femoris or diaphragmatic loss during mechanical ventilation (Fazzini et al. 2023). It is hard to limit or prevent – countless trials again into supplementation, high protein, rehabilitation, demonstrate a catabolic stress response that is not offset by increasing supply alone. There is a deliberate bodily choice to sacrifice muscle tissue because it feeds and regulates the immune response. IL-6 cytokines and the tryptophan pathway are just two examples of changes induced by inflammation that lead to muscle atrophy for the ‘greater good’.

How is This Affected by Frailty?

The proportion of elderly patients admitted to intensive care is increasing, with up to 40% presenting with pre-existing frailty (Moïsi et al. 2024). Frailty itself is an independent risk factor in the intensive care setting (Moïsi et al. 2024), associated with increased all-cause mortality and functional decline.

Frailty is typically scored in the UK with the Rockwood Frailty Score. Any coordinate of frailty correlates well with muscle bulk (e.g. measured in the psoas on imaging) (Ng et al. 2023), grip strength (Spiegowski et al. 2022), and in laparotomies, biomarkers affecting the transport of metabolic intermediates (Ng et al. 2023).

Given this association, an increased proportion of critical care patients will have signs of frailty, diminished muscle mass and a reduced physiological reserve to adapt to the catabolic state of critical illness. Furthermore, frailty is an independent risk factor for the degree of muscle loss in intensive care, when rectus femoris cross-sectional area measurements were performed seven days following intensive care admission. This suggests that the frail population not only start with a lower baseline muscle function but also suffer from accelerated losses in critical illness.

What are Emerging Therapies?

There are a myriad of emerging therapies, many of which are already in use – for example, flozins  – which have a therapeutic effect on metabolic ageing and muscle mass (Conte et al. 2025). IL-6 antagonists, with potential niche use within subtypes of critically ill patients, also reduce muscle loss (Wada et al. 2017). Other experimental treatments may derive from novel discoveries – for example, clock genes regulating circadian cell cogwork are heavily expressed in skeletal muscle (Lau et al. 2004).

Conclusion

It is clear when examining the effects of inflammation and metabolism that muscle sacrifice or signalling has an essential role to play. This is underpinned by studies demonstrating the intractable nature of muscle atrophy in critical illness and brings us to ask, how then, do we offset this parlous condition with the knowledge that we have now? Rivetingly, it may be the expansive network of diabetes research that can own this metabolic mayhem or hacking systems such as autophagy to delay or reduce frailty phenotypes in the first instance.

Conflict of Interest

None.