DUX4 overexpression in proliferating myoblasts induces an early response of the metabolic sensor AMPK

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Among DUX4-induced pathophysiological mechanisms, increased attention is being given to metabolic stress and mitochondrial dysfunction characterizing FSHD muscle cells. Among the key regulators of these processes, a decrease in PPARGC1A expression, which encodes the transcriptional coactivator PGC-1α was previously reported in immortalized FSHD patient-derived muscle cells. PGC-1α activity is dependent on post-translational modifications, notably phosphorylation by AMPK, a key metabolic sensor known to play a beneficial role in several myopathies. Here, given our expertise on AMPK, we further studied the impact of a boost of DUX4 expression on the AMPK-PGC1a axis with a first focus on the early response following the induction of DUX4 expression in LHCN-M2-iDUX4 myoblasts treated with doxycycline (6,18 and 24h). DUX4 induction increased ZSCAN4 (a direct target) and decreased MYOD1 and MYF5, validating our myoblast model. Moreover, oxidative stress was measured after DUX4 induction, and we see a significant increase in our groups. Interestingly, PPARGC1A expression was increased under our experimental conditions along with upregulation of AMPKα2 and regulatory subunits β1 and β2 in induced myoblasts. This could be a result of a compensatory response to cope to mitochondrial alterations. Further analysis must be performed to determine the exact role of these key factors.

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