Altered Expression of Myogenic Regulatory Factors in the Mouse Model of Amyotrophic Lateral Sclerosis

<i>Background:</i> In the superoxide dismutase 1 (SOD1)-G93A mouse model of amyotrophic lateral sclerosis (ALS), skeletal muscle is a key target of mutant SOD1 toxicity. However, the expression of factors that control the regenerative potential of the muscle is unknown in this model. <i>Objective:</i> To characterize the expression of satellite cell marker <i>Pax7</i> and myogenic regulatory factors (MRF) in skeletal muscle of SOD1-G93A mice at different stages of the disease. <i>Methods:</i> The expressions of <i>Pax7, Myod1, Myf5</i> and myogenin <i>(Myog)</i> were determined by quantitative real-time PCR and by Western blotting from the grouped gastrocnemius, quadriceps and soleus muscles of SOD1-G93A mice at presymptomatic, symptomatic and terminal stages of the disease, and from surgically denervated wild-type gastrocnemius muscles. <i>Results:</i><i>Pax7</i> mRNA and MYF5 protein were upregulated in presymptomatic mice, coinciding with increased muscle damage marker <i>Rrad</i> and chemokine <i>Ccl5.</i> All MRF transcripts and most proteins (excluding MYOG) were increased, starting from 3 months of age, simultaneously with increased expression of denervation marker Chrna1. However, in the terminal stage, no protein increase was evident for <i>Pax7</i> or any of the MRF despite the increased mRNA levels. The transcripts for chemokine <i>Ccl2</i> and chemokine receptor <i>Cxcr4 </i>were increased starting from the onset of symptoms. <i>Conclusions:</i> The characterization of <i>Pax7</i> and MRF in SOD1-G93A mice reveals a progressive induction of the myogenic program at the RNA level, but a blunted protein level response at late stages of the disease. Altered posttranscriptional and posttranslational mechanisms likely to operate, as well as the potential role of chemokine signaling in mutant SOD1 muscle, are discussed.