Stabilin-2 modulates the efficiency of myoblast fusion during myogenic differentiation and muscle regeneration

Abstract

Myoblast fusion is essential for the formation of skeletal muscle myofibres. Studies have shown that phosphatidylserine is necessary for myoblast fusion, but the underlying mechanism is not known. Here we show that the phosphatidylserine receptor stabilin-2 acts as a membrane protein for myoblast fusion during myogenic differentiation and muscle regeneration. Stabilin-2 expression is induced during myogenic differentiation, and is regulated by calcineurin/NFAT signalling in myoblasts. Forced expression of stabilin-2 in myoblasts is associated with increased myotube formation, whereas deficiency of stabilin-2 results in the formation of small, thin myotubes. Stab2-deficient mice have myofibres with small cross-sectional area and few myonuclei and impaired muscle regeneration after injury. Importantly, myoblasts lacking stabilin-2 have reduced phosphatidylserine-dependent fusion. Collectively, our results show that stabilin-2 contributes to phosphatidylserine-dependent myoblast fusion and provide new insights into the molecular mechanism by which phosphatidylserine mediates myoblast fusion during muscle growth and regeneration.

Mitochondrial glycerol 3‐phosphate dehydrogenase promotes skeletal muscle regeneration

“…At the same time, expressions of the satellite cell marker paired box protein 7 (PAX7; Zhang et al , ; Bi et al , ) and the satellite cell activation marker myoblast determination protein (MyoD; Zhang et al , ; Bi et al , ) were not different between the mGPDH −/− and WT mice (), which suggests that mGPDH has no significant effects on myoblast quantity and activation. However, the differentiation markers myogenin and myh3 (Park et al , ) were reduced in the mGPDH −/− mice (Fig J and K), which is consistent with our in vitro data and indicates that mGPDH deletion inhibits skeletal muscle regeneration by diminishing myoblast differentiation.…”

Sarcolipin deletion exacerbates soleus muscle atrophy and weakness in phospholamban overexpressing mice

“…When examining the phosphorylation status of nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) as a marker of calcineurin signaling, compared with WT we found that NFATc1 phosphorylation relative to total NFATc1 was significantly lower in Pln OE but not Pln OE / Sln KO soleus (Fig 5A). Calcineurin-mediated activation of NFATc1 increases the expression of stabilin-2; a phosphatidylserine receptor required for myoblast fusion [40]. Corresponding well with the significant dephosphorylation of NFATc1 only in the Pln OE mice, we found a significant elevation in stabilin-2 expression only in Pln OE soleus compared with WT (Fig 5B).…”

TMEM16F phospholipid scramblase mediates trophoblast fusion and placental development

“…Contrasting the prevailing view that PS exposure during cell-cell fusion is a consequence of apoptosis and caspase activation [17][18][19] , our experiments clearly demonstrate that apoptosis is not required for CaPLSase-mediated cell-cell fusion. Application of Q-VD, a pan-caspase inhibitor, has no effects on trophoblast fusion ( Figure 1D and 1E), suggesting that apoptosis and caspase-activated lipid scramblases play a dispensable role in PS exposure during trophoblast fusion.…”

“…types. The notion of PS exposure as an early hallmark of apoptosis led to the prevailing view of PS exposure during cell-cell fusion: apoptosis is responsible for PS exposure-mediated cell-cell fusion [17][18][19] .…”