Dexamethasone- and rapamycin-mediated mitochondrial dysfunction occurs independently of altered Yin Yang 1 expression...

Skeletal muscle is an indispensable tissue and loss of skeletal muscle mass and function can severely impact quality of life. Dexamethasone-treated C2C12 myotubes are an increasingly common model for studying skeletal muscle pathology (such as atrophy). While many features of this model are well-established (reduced myotube size, reduced anabolic signaling, and increased atrophic signaling), the mechanisms by which dexamethasone leads to mitochondrial dysfunction are less explored. This work assessed the effect of dexamethasone-mediated mitochondrial dysfunction on Yin Yang 1 (YY1) expression. YY1 interacts with various signaling pathways, including the mechanistic target of rapamycin (mTOR) and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (Ppargc1a/PGC-1α), all of which have been shown to be down-regulated following dexamethasone treatment.

C2C12 myotubes were treated with dexamethasone at either 50 μM or 100 μM, or rapamycin at 100 nM, or DMSO vehicle control for up to 24 h. Mitochondrial function was assessed by measuring oxygen consumption, mitochondrial content was measured using fluorescent staining, and related protein expression was determined via Western blot.

As expected, both dexamethasone and rapamycin independently reduced mitochondrial function and content. However, despite reduced mTOR activity, neither dexamethasone (at either concentration) or rapamycin had any effect on YY1 expression.

Given the interplay between YY1 and metabolic signaling cascades, we hypothesized dexamethasone would down-regulate YY1 as part of a milieu of depressed metabolism. However, because we observed reduced mitochondrial function and content independent of changes in YY1 abundance and activity, it appears that altered YY1 abundance is not a vital contributor during dexamethasone-mediated mitochondrial dysfunction.