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Neuromuscular junctions are stable in patients with cancer cachexia.

ABSTRACT: Cancer cachexia is a major cause of patient morbidity and mortality, with no efficacious treatment or management strategy. Despite cachexia sharing pathophysiological features with a number of neuromuscular wasting conditions, including age-related sarcopenia, the mechanisms underlying cachexia remain poorly understood. Studies of related conditions suggest that pathological targeting of the neuromuscular junction (NMJ) may play a key role in cachexia, but this has yet to be investigated in human patients. Here, high-resolution morphological analyses were undertaken on NMJs of rectus abdominis obtained from patients undergoing upper GI cancer surgery compared with controls (N = 30; n = 1,165 NMJs). Cancer patients included those with cachexia and weight-stable disease. Despite the low skeletal muscle index and significant muscle fiber atrophy (P < 0.0001) in patients with cachexia, NMJ morphology was fully conserved. No significant differences were observed in any of the pre- and postsynaptic variables measured. We conclude that NMJs remain structurally intact in rectus abdominis in both cancer and cachexia, suggesting that denervation of skeletal muscle is not a major driver of pathogenesis. The absence of NMJ pathology is in stark contrast to what is found in related conditions, such as age-related sarcopenia, and supports the hypothesis that intrinsic changes within skeletal muscle, independent of any changes in motor neurons, represent the primary locus of neuromuscular pathology in cancer cachexia.

SUBMITTER: Boehm I

PROVIDER: S-EPMC7269586 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Neuromuscular junctions are stable in patients with cancer cachexia.

Boehm Ines I Miller Janice J Wishart Thomas M TM Wigmore Stephen J SJ Skipworth Richard Je RJ Jones Ross A RA Gillingwater Thomas H TH

The Journal of clinical investigation 20200301 3

Cancer cachexia is a major cause of patient morbidity and mortality, with no efficacious treatment or management strategy. Despite cachexia sharing pathophysiological features with a number of neuromuscular wasting conditions, including age-related sarcopenia, the mechanisms underlying cachexia remain poorly understood. Studies of related conditions suggest that pathological targeting of the neuromuscular junction (NMJ) may play a key role in cachexia, but this has yet to be investigated in huma ...[more]

PMID: 31794435

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Project description:Desmin, the major intermediate filament (IF) protein in muscle cells, interlinks neighboring myofibrils and connects the whole myofibrillar apparatus to myonuclei, mitochondria, and the sarcolemma. However, desmin is also known to be enriched at postsynaptic membranes of neuromuscular junctions (NMJs). The pivotal role of the desmin IF cytoskeletal network is underscored by the fact that over 100 mutations of the human DES gene cause hereditary and sporadic myopathies and cardiomyopathies. A subgroup of human desminopathies comprises autosomal recessive cases resulting in complete abolition of desmin protein. In these patients, who display a more severe phenotype than the autosomal dominant cases, it has been reported that some individuals also suffer from a myasthenic syndrome in addition to the classical occurrence of myopathy and cardiomyopathy. Since further studies on the NMJ pathology is hampered by the lack of available human striated muscle biopsy specimens, we exploited homozygous desmin knock-out mice which closely mirror the striated muscle pathology of human patients lacking desmin protein. Here, we report on the impact of the lack of desmin on the structure and function of NMJs and on the transcription of genes coding for postsynaptic proteins. Desmin knock-out mice display a fragmentation of NMJs in soleus, but not in extensor digitorum longus muscle. Moreover, soleus muscle fibers show larger NMJs. Further, transcription levels of acetylcholine receptor (AChR) genes are increased in muscles from desmin knock-out mice, especially of the AChR subunit, which is known as a marker of muscle fiber regeneration. Electrophysiological recordings depicted a pathological decrement of nerve-dependent endplate potentials and a faster rise time of the nerve-independent miniature endplate potentials. The latter is indicating an enhanced opening time of the AChR channels. Our study highlights the essential role of desmin for the structural and functional integrity of mammalian neuromuscular junctions.

Project description:BackgroundThe cachexia index is a useful predictor for cancer cachexia and prognostic assessment. However, its use is limited because of high testing costs and complicated testing procedures. Thus, in this study, we aimed to develop a hand grip strength (HGS)-based cancer cachexia index (H-CXI) as a potential predictor of cancer cachexia and prognosis in patients with cancer.MethodsHere, 14 682 patients with cancer were studied, including the discovery (6592), internal validation (2820) and external validation (5270) cohorts. The H-CXI was calculated as [HGS (kg)/height (m)2 × serum albumin (g/L)]/neutrophil-to-lymphocyte ratio. The Kaplan-Meier method was used to create survival curves, and the log-rank test was used to compare time-event relationships between groups. A Cox proportional hazard regression model was used to determine independent risk factors for overall survival (OS). Logistic regression analysis was used to assess the association of the H-CXI with short-term outcomes and cancer cachexia.ResultsThere was a significant non-linear relationship between the H-CXI and OS in all cohorts. Patients with a low H-CXI had significantly lower OS than those with a high H-CXI in the discovery cohort (6-year survival percentage: 55.72% vs. 76.70%, log-rank P < 0.001), internal validation cohort (6-year survival percentage: 55.81% vs. 76.70%, log-rank P < 0.001), external validation cohort (6-year survival percentage: 56.05% vs. 75.48%, log-rank P < 0.001) and total cohort (6-year survival percentage: 55.86% vs. 76.27%, log-rank P < 0.001). Notably, the prognostic stratification effect of the H-CXI in patients with advanced-stage disease was more significant than that in patients with early-stage disease. The multivariate Cox proportional risk regression model confirmed that a low H-CXI negatively affected the prognosis of patients with cancer in the discovery cohort [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.71-0.80, P < 0.001], internal validation cohort (HR 0.79, 95 %CI 0.72-0.86, P < 0.001), external validation cohort (HR 0.84, 95% CI 0.79-0.89, P < 0.001) and total cohort (HR 0.80, 95% CI 0.77-0.83, P < 0.001). Multivariate logistic regression models showed that a low H-CXI was an independent risk factor predicting adverse short-term outcomes and cancer cachexia in patients with cancer.ConclusionsThe simple and practical H-CXI is a promising predictor for cancer cachexia and prognosis in patients with cancer.

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Neuromuscular junctions are stable in patients with cancer cachexia.

Publications

Neuromuscular junctions are stable in patients with cancer cachexia.

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