Cancer Cachexia and Skeletal Muscle Atrophy Mechanisms

Cancer cachexia is a multifactorial syndrome characterised by progressive loss of skeletal muscle mass, with or without concomitant loss of adipose tissue, driven by systemic inflammation, metabolic rewiring and disrupted proteostasis. Tumour-derived factors and pro-inflammatory cytokines such as interleukin-6 and tumour necrosis factor-α activate catabolic programmes in muscle, including the ubiquitin–proteasome system and autophagy–lysosome pathway. Transcription factors of the FoxO family and STAT3 integrate upstream signals, orchestrating gene networks that promote protein degradation and inhibit anabolic signalling through the IGF-1/Akt/mTOR axis. Mitochondrial dysfunction, oxidative stress and impaired organelle quality control further exacerbate muscle fibre atrophy. Beyond muscle, multi-organ crosstalk involving liver gluconeogenesis, white adipose tissue browning and alterations in appetite regulation compounds the energetic imbalance. Clinically, cachexia affects up to 80 per cent of advanced cancer patients, worsens treatment tolerance and underlies up to 20 per cent of cancer-related deaths. Despite its global impact, no pharmacological agent has yet been approved to counteract muscle wasting in this context, highlighting an urgent need for targeted interventions that restore proteostasis, suppress inflammation and rebalance energy metabolism.

Research from Nature Portfolio

Recent studies have refined our understanding of the signalling networks that regulate muscle mass in cachexia. A comprehensive analysis of muscle atrophy and hypertrophy mechanisms has delineated how mechanical, nutritional and inflammatory stimuli converge on key nodes such as mTOR, FoxO transcription factors and organelle quality-control systems to determine protein turnover and muscle function. In parallel, muscle-specific deletion of FoxO members has been shown to protect against atrophy by coordinately suppressing both autophagy–lysosome and ubiquitin–proteasome routes. This work identified novel FoxO-dependent ubiquitin ligases, including MUSA1 and SMART, as critical effectors of muscle proteolysis under catabolic stress, providing potential targets for therapeutic modulation.

Cancer Cachexia and Skeletal Muscle Atrophy Mechanisms publication trend

The graph below shows the total number of articles in cancer cachexia and skeletal muscle atrophy mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Cachexia: A complex metabolic syndrome in cancer characterised by involuntary weight loss, muscle wasting and systemic inflammation.

Ubiquitin–proteasome system: A major intracellular pathway for targeted protein degradation essential to muscle catabolism.

Autophagy–lysosome pathway: A degradative process that recycles cellular components and contributes to muscle protein breakdown.

FoxO transcription factors: Regulators of gene programmes that induce proteolytic systems and inhibit growth pathways during atrophy.

Adipose browning: The conversion of white fat to a thermogenic phenotype, increasing energy expenditure.

Extracellular vesicles: Membrane-bound particles released by cells that mediate intercellular communication and can transport cachexia-promoting factors.

References

1. GRP75 triggers white adipose tissue browning to promote cancer-associated cachexia. Signal Transduction and Targeted Therapy (2024).
2. Cancer cachexia: molecular mechanisms and treatment strategies. Journal of Hematology & Oncology (2023).
3. Mechanisms of muscle atrophy and hypertrophy: implications in health and disease. Nature Communications (2021).
4. Mechanisms of IGF-1-Mediated Regulation of Skeletal Muscle Hypertrophy and Atrophy. Cells (2020).
5. Regulation of autophagy and the ubiquitin–proteasome system by the FoxO transcriptional network during muscle atrophy. Nature Communications (2015).
6. Protein breakdown in muscle wasting: Role of autophagy-lysosome and ubiquitin-proteasome. The International Journal of Biochemistry & Cell Biology (2013).
7. STAT3 Activation in Skeletal Muscle Links Muscle Wasting and the Acute Phase Response in Cancer Cachexia. PLOS ONE (2011).
8. Inflammation and Skeletal Muscle Wasting During Cachexia. Frontiers in Physiology (2020).
9. Cancer cachexia and its pathophysiology: links with sarcopenia, anorexia and asthenia. Journal of Cachexia Sarcopenia and Muscle (2020).