Cancer cachexia-induced muscle atrophy: evidence for alterations in microRNAs important for muscle size

Abstract

Muscle atrophy is a hallmark of cancer cachexia resulting in impaired function and quality of life and cachexia is the immediate cause of death for 20-40% of cancer patients. Multiple microRNAs (miRNAs) have been identified as being involved in muscle development and atrophy; however, less is known specifically on miRNAs in cancer cachexia. The purpose of this investigation was to examine the miRNA profile of skeletal muscle atrophy induced by cancer cachexia to uncover potential miRNAs involved with this catabolic condition. Phosphate-buffered saline (PBS) or Lewis lung carcinoma cells (LLC) were injected into C57BL/6J mice at 8 wk of age. LLC animals were allowed to develop tumors for 4 wk to induce cachexia. Tibialis anterior muscles were extracted and processed to isolate small RNAs, which were used for miRNA sequencing. Sequencing results were assembled with mature miRNAs, and functions of miRNAs were analyzed by Ingenuity Pathway Analysis. LLC animals developed tumors that contributed to significantly smaller tibialis anterior muscles (18.5%) and muscle cross-sectional area (40%) compared with PBS. We found 371 miRNAs to be present in the muscle above background levels. Of these, nine miRNAs were found to be differentially expressed. Significantly altered groups of miRNAs were categorized into primary functionalities including cancer, cell-to-cell signaling, and cellular development among others. Gene network analysis predicted specific alterations of factors contributing to muscle size including Akt, FOXO3, and others. These results create a foundation for future research into the sufficiency of targeting these genes to attenuate muscle loss in cancer cachexia.

α‐Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway

“…Excessive protein degradation is the main cause for skeletal muscle atrophy, which is harmful to human health and leads to muscle fatigue and reduced life span (28)(29)(30)(31). Abnormal protein degradation and muscle atrophy generally occur with genetic mutation (DMD) (32), hormone exposure (glucocorticoid) (33), or disease (cachexia) (34). Many studies have shown that appropriate exercise can induce muscle hypertrophy and is also an effective way to rescue muscle atrophy (35)(36)(37).…”

Uncoupling protein 1 expression in adipocytes derived from skeletal muscle fibro/adipogenic progenitors is under genetic and hormonal control

“…It would be also important to assess intramuscular Ucp1 expression in other models of atrophy. This will, however, likely require experiments with additional animal species because fatty infiltration is generally not observed during denervation atrophy [66][67][68][69] or cancer cachexia 65,[70][71][72] in mice.…”

Tumour‐derived transforming growth factor‐β signalling contributes to fibrosis in patients with cancer cachexia

“…Chronic inflammation has been reported in the majority of patients with CAC and causes disruption of morphofunctional aspects of many tissues, such as the brain, the adipose tissue, and the muscle, while also affecting tumour biology . The secretory profile of the tumour may be associated with cachexia–muscle wasting, as proposed by de Matos‐Neto et al .…”

“…3 Clinically, CAC consists of chronic systemic inflammation and catabolism, leading to reduction of quality of life, diminished treatment tolerance, tumour metabolic reprograming, and, consequently, decreased survival. [4][5][6] Chronic inflammation has been reported in the majority of patients with CAC 7 and causes disruption of morphofunctional aspects of many tissues, such as the brain, 8,9 the adipose tissue, [10][11][12][13] and the muscle, 14,15 while also affecting tumour biology. 5,16 The secretory profile of the tumour may be associated with cachexia-muscle wasting, as proposed by de Matos-Neto et al.…”