Duchenne muscular dystrophy (DMD) is a deadly X-linked recessive genetic disorder caused by dystrophin gene mutations, affecting 1 in 5000 males. The absence of functional dystrophin leads to sarcolemma weakening, regeneration failure, muscle degeneration, and weakness. However, the signaling mechanisms that initiate myonecrosis, inflammation, and muscle damage remain elusive.
Transforming growth factor β-activated kinase 1 (TAK1) is an important signaling protein that regulates cell survival, growth, and inflammation. Previously, we have demonstrated that supraphysiological activation of TAK1 in the skeletal muscle of adult mice promotes myofiber growth by increasing protein synthesis. TAK1 activation stimulates the protein translation machinery by phosphorylating elongation initiation factor 4E (eIF4E) and ribosomal protein S6 (rpS6). Conversely, muscle-specific deletion of TAK1 destabilizes neuromuscular junctions, dysregulates Smad signaling, and causes muscle atrophy in adult mice. However, the role of TAK1 in muscle disorders remained unknown.
In the present study, we demonstrate that TAK1 signaling has a dual effect in the skeletal muscle of mdx mice, a model of DMD. TAK1 remains highly activated in the skeletal muscle of young mdx mice when muscle necrosis is at its peak. Targeted inducible inactivation of TAK1 mitigates muscle injury, and accumulation of macrophages, and ameliorates histopathology. It was accompanied by inhibition of the necroptosis pathway and activation of autophagy, Notch, and Wnt signaling. Interestingly, inactivation of TAK1 also led to a significant reduction in myofiber size and muscle contractile functions in both young and adult mdx mice.
Our results show that forced activation of TAK1 in the skeletal muscle of mdx mice through intramuscular injection of AAV6 vectors expressing TAK1 and TAB1 stimulates myofiber growth without adverse effects on muscle histopathology in adult mdx mice. Through the temporal regulation of TAK1 expression, targeted inactivation during the necrotic stage followed by activation in the regenerating phase, our study demonstrates amelioration in disease progression and improvement in myofiber size in the skeletal muscle of mdx mice.