Cancer cachexia impairs neural respiratory drive in hypoxia but not hypercapnia

Abstract

Background Cancer cachexia is an insidious process characterized by muscle atrophy with associated motor deficits, including diaphragm weakness and respiratory insufficiency. Although neuropathology contributes to muscle wasting and motor deficits in many clinical disorders, neural involvement in cachexia‐linked respiratory insufficiency has not been explored. Methods We first used whole‐body plethysmography to assess ventilatory responses to hypoxic and hypercapnic chemoreflex activation in mice inoculated with the C26 colon adenocarcinoma cell line. Mice were exposed to a sequence of inspired gas mixtures consisting of (i) air, (ii) hypoxia (11% O 2 ) with normocapnia, (iii) hypercapnia (7% CO 2 ) with normoxia, and (iv) combined hypercapnia with hypoxia (i.e. maximal chemoreflex response). We also tested the respiratory neural network directly by recording inspiratory burst output from ligated phrenic nerves, thereby bypassing influences from changes in diaphragm muscle strength, respiratory mechanics, or compensation through recruitment of accessory motor pools. Results Cachectic mice demonstrated a significant attenuation of the hypoxic tidal volume (0.26mL±0.01mL vs 0.30mL±0.01mL; p<0.05), breathing frequency (317±10bpm vs 344±6bpm; p<0.05) and phrenic nerve (29.5±2.6% vs 78.8±11.8%; p<0.05) responses. On the other hand, the much larger hypercapnic tidal volume (0.46±0.01mL vs 0.46±0.01mL; p>0.05), breathing frequency (392±5bpm vs 408±5bpm; p>0.05) and phrenic nerve (93.1±8.8% vs 111.1±13.2%; p>0.05) responses were not affected. Further, the concurrent hypercapnia/hypoxia tidal volume (0.45±0.01mL vs 0.45±0.01mL; p>0.05), breathing frequency (395±7bpm vs 400±3bpm; p>0.05), and phrenic nerve (106.8±7.1% vs 147.5±38.8%; p>0.05) responses were not different between C26 cachectic and control mice. Conclusions Breathing deficits associated with cancer cachexia are specific to the hypoxic ventilatory response and, thus, reflect disruptions in the hypoxic chemoafferent neural network. Diagnostic techniques that detect decompensation and therapeutic approaches that support the failing hypoxic respiratory response may benefit patients at risk for cancer cachectic‐associated respiratory failure.

Mitochondrial Function and Protein Turnover in the Diaphragm are Altered in LLC Tumor Model of Cancer Cachexia

“…A notable limitation of the present study is that we were unable to directly measure diaphragm and respiratory function during this study. However, many prior works have noted alterations to diaphragm function in murine models of cancer cachexia including lower fiber cross sectional area, deteriorations in contractile efficiency, and altered ventilatory responses [ 18 , 40 ]. Taken together, although we did not specifically measure ventilatory function in the present study, it is plausible to infer that these same detriments to diaphragm health occurred with the onset of cachexia (~3–4 weeks [ 24 , 28 ]).…”

Corticospinal Control of Human Locomotion as a New Determinant of Age-Related Sarcopenia: An Exploratory Study

“…Voluntary activation, defined as "the level of voluntary drive during an effort" [105,106] is especially diminished in older-old individuals [107][108][109] and up to one third of losses in force production capacity may be explained by voluntary activation [110]. A recent study on cancer cachexia, which clinically presents with muscle atrophy and associated motor deficits, found that impaired neural respiratory drive was a significant contributor to respiratory muscles insufficiency [111]. Based on research findings and theoretical reasoning this has led to questioning of the conceptualizing of sarcopenia as primarily being a condition tied to the muscular system.…”

Cancer Cachexia and Related Metabolic Dysfunction

“…A study in patients with stage III and IV of head and neck cancer assessed the reduction in LBM and fat mass after one month of concurrent chemo-radiation treatment and found a reduction by 71.7% and 28.3%, respectively [35]. In addition, muscle wasting is not an exclusive feature of skeletal muscle involved in locomotion, it has also been shown to affect respiratory muscles and even myocardium in patients with chronic disease-associated wasting [36][37][38]. Additionally, the progression of tumor cells, as well as cardiotoxicity induced by cancer treatment, may lead to a condition called "cardiac cachexia" that is characterized by cardiac atrophy, fibrosis, and myocardial dysfunction [39].…”