Transforming Growth Factor beta 1 signaling is altered in the spinal cord and muscle of amyotrophic lateral sclerosis mice and patients

Gender differences characterize amyotrophic lateral sclerosis (ALS). Since ALS patients have increased circulating levels of transforming growth factor beta 1 (TGFB1), here we analysed gender and disease progression related modification of TGFB1 and its related signaling molecules in spinal cord and skeletal muscle of ALS mice and in muscle biopsies from sporadic ALS patients. At presymptomatic (PS) stage Tgfb1 expression is reduced in mouse spinal cord, but is increased selectively in male skeletal muscle. At symptomatic (S) stage Tgfb1 is induced both in mouse spinal cord and muscle, as well as in muscle of ALS patients. Tgfbr2 levels are induced only in mouse spinal cord. Smad2 and Smad4 are decreased in mouse spinal cord and muscle, but SMAD2 protein levels are augmented selectively in male mouse muscle. Smad3 mRNA and SMAD3 protein are increased in mouse muscle. Genes controlled by TGFB1 in muscle (Pax7, Collagen1a1 and Fibronectin) are reduced both in male and female ALS mice at S stage. Thus, TGFB1 modulation may serve as a novel therapeutic target for ALS.