Abstract
Denervation of skeletal muscles initiates a cascade of cellular events that can lead to muscle atrophy, however, the underlying mechanism is controversial. In the present study, by using techniques including real-time PCR, immunoblotting, fluorescent in situ hybridization, and enzyme-linked immunosorbent, we demonstrated that VEGFR2 was distinctively cross-linked with MyHCI in gastrocnemius, and MyHC2B in soleus, which was likely responsible for activation of receptor tyrosine kinases including growth factor receptor-bound 2, phospholipase Cγ, p85, Vav, and human epidermal growth factor receptor 2. When challenged with muscle mobilization, in gastrocnemius, VEGFR2 was preferentially translocated into mitochondria, which resulted in activation of NAD+ - SIRT1 and remodel of macrophage polarization. Alternatively, in soleus, VEGFR2 was targeted to ER, this shortrange transport eventually enhanced T cell activation including miR181a expression and IL-15 release. Importantly, M1 macrophage polarization and T cell activation mostly induced disrupted muscular homeostasis, the cellular processes might make soleus more vulnerable to insults than gastrocnemius. Therefore, endocytic delivery of VEGFR2 by myosin might precipitate distinctive cellular environment in the mobilized gastrocnemius and soleus, mitochondrial gene transcription and T cell activation were proposed to involve in the phenotype-dependent alterations respectively.
Highlights
Skeletal muscle comprises up to 40% of human body mass, and is a highly ordered, structurally stable tissue whose function is dependent on an intact nerve supply
Immunoprecipitation experiments showed that the interaction between MyHCI and VEGFR2 was biphasically modulated during muscle mobilization, namely, increased within 7 days and gradually decreased, the alteration occurred on gastrocnemius but not soleus (Figure 1A and 1B)
In gastrocnemius, Western Blot analysis indicated that expressions of receptor tyrosine kinase-related molecules including growth factor receptor-bound (Grb)2, phospholipase (PL) Cγ, P85, Vav, and human epidermal growth factor receptor (HER)2 were markedly increased on days 1-7 following muscle mobilization, with levels that were 2.1-3.0 fold higher than control values (Figure 1C and 1D)
Summary
Skeletal muscle comprises up to 40% of human body mass, and is a highly ordered, structurally stable tissue whose function is dependent on an intact nerve supply. Our previous observation indicated that vascular endothelial growth factor (VEGF)-VEGF receptor (R) signaling was initiated during muscle denervation, which was under the control of muscular inflammation and mitochondrial biogenesis, and accompanied with ensuing changes in the motor endplate [10,11,12]. Motor endplates on fast and slow muscle fibers show distinct transmitter release characteristics [25]. The present study is designed to investigate the association of short-range VEGFR2 cargo by myosin and functional muscular stabilization during muscle mobilization. A better understanding of phenotype-dependent alterations in muscle would enable the development of new agents to combat degenerative muscular disorders
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