Abstract
Homeobox A9 (HOXA9), the expression of which is promoted by mixed lineage leukemia 1 (MLL1) and WD-40 repeat protein 5 (WDR5), is a homeodomain-containing transcription factor that plays an essential role in regulating stem cell activity. HOXA9 has been found to inhibit skeletal muscle regeneration and delay recovery after muscle wounding in aged mice, but little is known about its role in denervated/reinnervated muscles. We performed detailed time-dependent expression analyses of HOXA9 and its promoters, MLL1 and WDR5, in rat gastrocnemius muscles after the following three types of sciatic nerve surgeries: nerve transection (denervation), end-to-end repair (repair), and sham operation (sham). Then, the specific mechanisms of HOXA9 were detected in vitro by transfecting primary satellite cells with empty pIRES2-DsRed2, pIRES2-DsRed2-HOXA9, empty pPLK/GFP-Puro, and pPLK/GFP-Puro-HOXA9 small hairpin RNA (shRNA) plasmids. We found, for the first time, that HOXA9 protein expression simultaneously increased with increasing denervated muscle atrophy severity and that upregulated MLL1 and WDR5 expression was partly associated with denervation. Indeed, in vitro experiments revealed that HOXA9 inhibited myogenic differentiation, affected the best known atrophic signaling pathways, and promoted apoptosis but did not eliminate the differentiation potential of primary satellite cells. HOXA9 may promote denervated muscle atrophy by regulating the activity of satellite cells.
Highlights
HOXA9 (Homeobox A9), whose expression is promoted by MLL1 (Mixed Lineage Leukemia 1) and WDR5 (WD-40 repeat protein 5), is a homeodomain-containing transcription factor which plays an essential role in regulating stem cell activity
We found that HOXA9 expression was synchronous with the severity of muscle atrophy, as well as the upregulation of MLL1 and WDR5 associated with the denervation state to some extent
Experiments with primary satellite cells revealed that HOXA9 inhibited myogenic differentiation, but not destroy the differentiation potential, influenced the best-known atrophic pathways, and promoted apoptosis
Summary
HOXA9 (Homeobox A9), whose expression is promoted by MLL1 (Mixed Lineage Leukemia 1) and WDR5 (WD-40 repeat protein 5), is a homeodomain-containing transcription factor which plays an essential role in regulating stem cell activity. Resulting from the imbalance between the synthesis and degradation of myoprotein, myofibers atrophy of myofibers progressed rapidly in diameter, mass, weight, and strength after denervation [4, 5]. This atrophy is widely accepted to be induced after activation of two well-known muscle-specific ubiquitin ligases, muscle RING finger-1 (MuRF-1) and muscle atrophy F-Box 1 (MAFbx, or Atrogin-1) [6]. Inhibition of FoxO3a and NF-κB prevented atrophy [11]
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