Voluntary exercise does not improve muscular properties or functional capacity during C26-induced cancer cachexia in mice

Abstract

Exercise training is considered as a potential intervention to counteract muscle degeneration in cancer cachexia. However, evidence to support such intervention is equivocal. Therefore, we investigated the effect of exercise training, i.e. voluntary wheel running, on muscle wasting, functional capacity, fiber type composition and vascularization during experimental cancer cachexia in mice. Balb/c mice were injected with PBS (CON) or C26 colon carcinoma cells to induce cancer cachexia (C26). Mice had free access to a running wheel in their home cage (CONEX and C26EX, n=8-9) or were sedentary (CONS and C26S, n=8-9). Mice were sacrificed 18 days upon tumor cell injection. Immunohistochemical analyes were performed on m. gastrocnemius and quadriceps, and ex vivo contractile properties were assessed in m. soleus and extensor digitorum longus (EDL). Compared with CON, C26 mice exhibited body weight loss (~20%), muscle atrophy (~25%), reduced grip strength (~25%), and lower twitch and tetanic force (~20%) production in EDL but not in m. soleus. Furthermore, muscle of C26 mice were characterizd by a slow-to-fast fiber type shift (type IIx fibers: +57%) and increased capillary density (~30%). In C26 mice, wheel running affect neither body weight loss, nor muscle atrophy or functional capacity, nor inhibited tumor growth. However, wheel running induced a type IIb to type IIa fiber shift in m. quadriceps from both CON and C26, but not in m. gastrocnemius. Wheel running does not exacerbate muscular degeneration in cachexic mice, but, when voluntary, is insufficient to improve the muscle phenotype.

Moderate Intensity Endurance and Resistance Exercise Attenuates Cachexia in Tumor-bearing Mice

“…All RT animals were able to reach food and water throughout the study, and no significant differences in food consumption were observed between any of the experimental groups (data not shown). All animals inoculated with C26 carcinoma cells developed tumors and none of the exercise interventions significantly affected tumor mass when compared to SED+C26 (Table I), which is consistent with other published reports (32). Heart and liver masses were significantly reduced in SED+C26 versus SED+CON (p<0.05), while no significant changes existed in soleus mass across all groups.…”

“…Prior to injection, mice were anesthetized using isoflurane by inhalation, and maintained under anesthesia during the time necessary to perform the tumor inoculation. Cells were injected subcutaneously, dorsally, between the scapulae (31)(32)(33). Animals and tumors were monitored daily for end point criteria, including relative tumor mass, significant loss in body mass, body score condition, and tumor ulceration.…”

Skeletal Muscle Sensitivity to Wasting Induced by Urothelial Carcinoma

“…Nonetheless, since the tumor-bearing mice assessed were severely cachectic, with a 30% reduction in their BW, this means that the animals presented an advanced pro-catabolic state, which was not suitable for this type of comparison. Corroborating this notion, other two studies involving severely cachectic C-26 mice showed a similar reduction in the muscle weight for fast-glycolytic (EDL and GAST) and slow-oxidative (SOL) muscles, highlighting the development of a systemic wasting pattern in this later stage of the disease [16,32].…”

“…However, conflicting evidence remains to whether there is a selective loss of myofibers or when all skeletal muscles are equally affected by cancer-induced wasting [13]. Interestingly, while some studies observed a selective atrophy of fast glycolytic muscles compared to slow oxidative muscles [14,15], other authors found that type I fibers were more affected by cance rin duced wasting [16] or that cancer significantly and diaphragm muscles were collected from all animals. For cross-sectional area and myonuclear domain analysis, muscle sections were stained with hematoxylin and eosin, and for collagen deposition assessment, muscle sections were stained with picrosirius red.…”

Impact of cancer cachexia on respiratory muscle function and the therapeutic potential of exercise

“…Whereas cachexia is associated with an increase in protein degradation and concurrent decrease in protein synthesis, exercise may work to combat the adverse effects of the condition, whilst simultaneously increasing lean tissue mass. Contradictory to this, a recent study demonstrated that voluntary exercise was ineffective in improving the muscle phenotype of cachectic C26 mice (Hiroux et al., 2021 ). Additionally, it has been hypothesised that increased energy demand due to tumour burden elevates the risk of over‐reaching (Allan et al., 2022 ), an acute instance of insufficient recovery following exercise which if not recognised and accommodated for can progress to overtraining syndrome (Urhausen & Kindermann, 2002 ).…”