Cachexia does not induce loss of myonuclei or muscle fibres during xenografted prostate cancer in mice

Abstract

Aim: Cachexia is a severe wasting disorder involving loss of body-and muscle mass reducing survival and quality of life in cancer patients. We aim at determining if cachexia is a mere perturbation of the protein balance or if the condition also involves a degenerative loss of myonuclei within the fibre syncytia or loss of whole muscle fibres. Methods: We induced cachexia by xenografting PC3 prostate cancer cells in nu/nu mice. Six weeks later, we counted myonuclei by in vivo microscopic imaging of single live fibres in the extensor digitorum longus muscle (EDL), and the EDL, soleus and tibialis anterior muscles were also harvested for ex vivo histology. Results: The mice lost on average 15% of the whole-body wt. The muscle wet weight of the glycolytic, fast EDL was reduced by 14%, the tibialis anterior by 17%, and the slow, oxidative soleus by 6%. The fibre cross-sectional area in the EDL was reduced by 21% with no loss of myonuclei or any significant reduction in the number of muscle fibres. TUNEL-positive nuclei or fibres with embryonic myosin were rare both in cachectic and control muscles, and haematoxylin-eosin staining revealed no clear signs of muscle pathology. Conclusion: The data suggest that the cachexia induced by xenografted prostate tumours induces a pronounced atrophy not accompanied by a loss of myonuclei or a loss of muscle fibres. Thus, stem cell related treatment might be redundant, and the quest for treatment options should rather focus on intervening with intracellular pathways regulating muscle fibre size. K E Y W O R D Satrophy, cachexia, cancer, myonuclei, skeletal muscle

Google maps for tissues: Multiscale imaging of biological systems and disease

“…4 Parametric MRI enables in vivo temperature mapping that opens an entirely new imaging driven research field of thermal phenotyping. 9 Utilizing in vivo microscopy of single muscle fibres, as well as conventional immunohistochemical ex vivo analysis, the authors detected no significant fibre loss and no reduction in myonuclear number in spite of a 21% reduction in fibre size. 5 On the mesoscopic scale emerging photoacoustic and ultrasound (US) imaging present an alternative to MRI.…”

“…Other highlights of DCE-MRI applications include monitoring of microcirculation to evaluate the role of exchange protein activated by cyclic adenosine monophosphate 1 in the response of transvascular fluid exchange to histamine in mice. 9 Single live fibres in the extensor digitorum longus muscle of mice were injected a solution containing oligonucleotides that serves as an intravital nuclear dye for counting myonuclei. The relevance of MR thermometry for the study of metabolically active brown adipose tissue in humans inspired a debate which is formed around the question whether skin temperature may not yield human brown adipose tissue activity in diverse populations because of the shortcomings and physiological confounders of infrared based thermometry.…”

“…The relevance of MR thermometry for the study of metabolically active brown adipose tissue in humans inspired a debate which is formed around the question whether skin temperature may not yield human brown adipose tissue activity in diverse populations because of the shortcomings and physiological confounders of infrared based thermometry. 9 It was concluded that with no loss of cells or myonuclei, targets for therapeutic interventions could be narrowed down to intracellular signalling pathways of the atrophying muscle fibres. Recent work offered a fascinating depiction of how US approaches can extend the spectrum of clinical applications into the domain of basic and applied physiological research.…”

“…5 On the mesoscopic scale emerging photoacoustic and ultrasound (US) imaging present an alternative to MRI. 9 In vivo Ca 2+ imaging is a powerful tool in physiology, which provides temporal resolution at the millisecond range and spatial resolution at micrometer range. A striking example from human integrative muscle physiology revealed that a reduction in activation level reduces residual force depression in tibialis anterior muscle.…”

“…8 Winje et al used microscopic imaging to address the question if cachexia-a severe wasting disorder including muscle atrophy-is a mere perturbation of the protein balance or if the condition also involves a degenerative loss of myonuclei within the fibre syncytia or loss of whole muscle fibres. 9 Single live fibres in the extensor digitorum longus muscle of mice were injected a solution containing oligonucleotides that serves as an intravital nuclear dye for counting myonuclei. 9 Utilizing in vivo microscopy of single muscle fibres, as well as conventional immunohistochemical ex vivo analysis, the authors detected no significant fibre loss and no reduction in myonuclear number in spite of a 21% reduction in fibre size.…”