FTO is required for myogenesis by positively regulating mTOR-PGC-1α pathway-mediated mitochondria biogenesis

Abstract

Global germ line loss of fat mass- and obesity-associated (FTO) gene results in both the reduction of fat mass and lean mass in mice. The role of FTO in adipogenesis has been proposed, however, that in myogenesis has not. Skeletal muscle is the main component of body lean mass, so its connection with FTO physiologic significance need to be clarified. Here, we assessed the impact of FTO on murine skeletal muscle differentiation by in vitro and in vivo experiments. We found that FTO expression increased during myoblasts differentiation, while the silence of FTO inhibited the differentiation; in addition, skeletal muscle development was impaired in skeletal muscle FTO-deficient mice. Significantly, FTO-promoted myogenic differentiation was dependent on its m6A demethylase activity. Mechanically, we found that FTO downregulation suppressed mitochondria biogenesis and energy production, showing as the decreased mitochondria mass and mitochondrial DNA (mtDNA) content, the downregulated expression of mtDNA-encoding genes and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) gene, together with declined ATP level. Moreover, the involvement of mTOR-PGC-1α pathway in the connection between FTO and muscle differentiation is displayed, since the expression of FTO affected the activity of mTOR and rapamycin blocked FTO-induced PGC-1α transcription, along with the parallel alteration pattern of FTO expression and mTOR phosphorylation during myoblasts differentiation. Summarily, our findings provide the first evidence for the contribution of FTO for skeletal muscle differentiation and a new insight to study the physiologic significance of RNA methylation.

The m6A‐epitranscriptomic signature in neurobiology: from neurodevelopment to brain plasticity

“…), and skeletal muscle myoblast differentiation (Wang et al . ), all of which suggest the general importance of FTO in development. Consistent with this notion, loss of FTO function in mice and human leads to postnatal growth retardation, including smaller brain volume (Boissel et al .…”

“…; Wang et al . ). Given that FTO undergoes nucleocytoplasmic shuttling in cells, it is conceivable that FTO may play a key role in modulating the mTORC1 signaling pathway in the cytoplasm (Russell and Morgan ; Gulati et al .…”

N6‐methyladenosine demethylase FTO suppresses clear cell renal cell carcinoma through a novel FTO‐PGC‐1α signalling axis

“…41 Recent studies have demonstrated that meclofenamic acid, a highly selective inhibitor of FTO, reduce ROS accumulation and apoptosis, 42 and that FTO regulates mitochondrial function. 35,36 We have been suggested that (Figure 4A,B).…”

“…However, the impact of FTO, especially as an RNA demethylase, in mitochondrial biogenesis, oxidative stress and ccRCC progression remain elusive. Importantly, recent reports suggest that FTO regulate mitochondria content through mediating mitochondrial fusion, fission and biogenesis‐associated genes expression as a N6‐methyladenosine RNA demethylase . To the point, we aim to explore the biological function of FTO in the post‐transcriptional modification of mitochondrial biogenesis and its subsequent influence in ccRCC and also explore the underlying molecular mechanism through identifying its key mRNA targets.…”

Phosphoregulation on mitochondria: Integration of cell and organelle responses

“…Alternatively, mTOR may have a role in OMM signaling through interplay with AKAP‐1, wherein mitochondrial PKA signaling may influence mTOR activity . It is clear that mTOR signaling is highly integrated with mitochondria physiology …”