NF-κB–mediated Pax7 dysregulation in the muscle microenvironment promotes cancer cachexia

Abstract

Cachexia is a debilitating condition characterized by extreme skeletal muscle wasting that contributes significantly to morbidity and mortality. Efforts to elucidate the underlying mechanisms of muscle loss have predominantly focused on events intrinsic to the myofiber. In contrast, less regard has been given to potential contributory factors outside the fiber within the muscle microenvironment. In tumor-bearing mice and patients with pancreatic cancer, we found that cachexia was associated with a type of muscle damage resulting in activation of both satellite and nonsatellite muscle progenitor cells. These muscle progenitors committed to a myogenic program, but were inhibited from completing differentiation by an event linked with persistent expression of the self-renewing factor Pax7. Overexpression of Pax7 was sufficient to induce atrophy in normal muscle, while under tumor conditions, the reduction of Pax7 or exogenous addition of its downstream target, MyoD, reversed wasting by restoring cell differentiation and fusion with injured fibers. Furthermore, Pax7 was induced by serum factors from cachectic mice and patients, in an NF-κB-dependent manner, both in vitro and in vivo. Together, these results suggest that Pax7 responds to NF-κB by impairing the regenerative capacity of myogenic cells in the muscle microenvironment to drive muscle wasting in cancer.

High CO2 Levels Cause Skeletal Muscle Atrophy via AMP-activated Kinase (AMPK), FoxO3a Protein, and Muscle-specific Ring Finger Protein 1 (MuRF1)

“…3), which represents a tissue response to myofiber injury (34). Although skeletal muscle atrophy has not classically been associated to cellular damage and repair but to an imbalance of protein turnover, a recent study shows that cancer-associated muscle atrophy is characterized by cellular injury and repair with activation and proliferation of satellite cells (42). Therefore, our finding of nuclear centralization could similarly suggests myofiber response to high CO 2 -mediated injury.…”

Microvesicles containing miRNAs promote muscle cell death in cancer cachexia viaTLR7

“…Primary myoblasts were isolated as previously described (18) and were preplated twice using noncoated tissue culture dishes and then cultured either on a matrigel-coated 96-well plate for Trypan blue and 3-(4,5-dimethylthiazol-2-yl)-2,5-dipheniltetrazolium bromide (MTS) assay reading at the indicated points or on a matrigel-coated 12-well plate for protein and RNA analysis.…”

“…In both tumor-bearing mice and patients with pancreatic cancer and weight loss, we found that the transcription factor, Pax7, which controls the selfrenewal of muscle stem cells, was persistently expressed. This sustained expression of Pax7 caused committed stem cells to be impaired in their differentiation program, resulting in their inability to fuse with damaged myofibers, which in turn enhanced muscle atrophy (18). These results showed that events in the muscle microenvironment are important in tumor-induced muscle wasting.…”

Novel investigational drugs mimicking exercise for the treatment of cachexia

“…The levels of Pax7, a marker of SC proliferation, and those of myogenin, an indicator of ongoing differentiation, respectively increase and decrease, respectively, in the muscle of mice bearing the colon 26 carcinoma (C26) as well as in cancer patients, suggesting that myogenic precursors accumulate in the skeletal muscle of tumor hosts (22) (23) (24) . This process appears to depend on the maintenance of elevated Pax7 expression, apparently related to activation of the transcription factor NF-κB (23) . Impaired myogenesis is associated with enhanced signaling through the stress kinase ERK, which is known to maintain cells in an undifferentiated state (22) .…”