Abstract
Restoring the contractile function of long-term denervated skeletal muscle (SKM) cells is difficult due to the long period of denervation, which causes a loss of contractility. Although sensory innervation is considered a promising protective approach, its effect is still restricted. In this study, we introduced insulin-like growth factor-1 (IGF-1) as an efficient protective agent and observed that IGF-1 potentiated the effects of sensory protection by preventing denervated muscle atrophy and improving the condition of denervated muscle cells in vivo and in vitro. IGF-1-induced Akt phosphorylation suppressed the mitochondrial outer-membrane protein Mul1 expression, which is a key step on preserving contractile property of sensory innervated SKM cells. Mul1 overexpression interfered with the balance between mitochondrial fusion and fission and was a key node for blocking the effects of IGF-1 that preserved the contractility of sensory-innervated SKM cells. Activation of AMP-activated protein kinase α (AMPKα), a mitochondrial downstream target, could block the effects of IGF-1. These data provide novel evidence that might be applied when searching for new approaches to improve the functional condition of long-term denervated SKM cells by increasing sensory protection using the IGF-1 signalling system to modulate the balance between mitochondrial fusion and fission.
Highlights
Degradation and improving synthesis[11,12]
The present study tests the following hypotheses: (1) IGF-1 may have more obvious effects on sensory-innervated skeletal muscle (SKM) cells than on denervated SKM cells in vivo and in vitro; (2) IGF-1-induced Akt phosphorylation is a key step in the preservation of the contractility of sensory-innervated SKM cells; (3) IGF-1-induced Akt phosphorylation may suppress the expression of the mitochondrial outer-membrane protein Mul[1], and overexpression of Mul[1] may block the effects of IGF-1 on the preservation of the contractility of sensory-innervated SKM cells; (4) Mul[1] expression may interfere with the balance between mitochondrial fusion and fission in sensory-innervated SKM cells; and (5) the mitochondrial downstream target AMPKαmay be inhibited by IGF-1, and activation of AMPKαmay block the effects of IGF-1 on the preservation of the contractility of sensory-innervated SKM cells
Sensory protection has been suggested as a promising technique when motor nerve repair is delayed or when injury occurs at a proximal point[4]
Summary
Degradation and improving synthesis[11,12]. Increased phosphorylation levels of Akt have induced SKM hypertrophy and have prevented denervated muscle atrophy[13]. The actions of Mul[1] in sensory-innervated SKM cells and its connection to the IGF-1 modulation of these cells are still unknown Another mechanism resulting in muscle atrophy is the activation of AMP-activated protein kinase α(AMPKα) induced by a decrease in energy production or an enhancement in mitochondrial fission. Mitochondrial fragmentation-activated AMPKαmay induce the expression of atrophy-related genes, atrogin-1 and muscle RING finger 1 (MuRF1), which results in muscle mass loss[21,22,23,24,25] Whether this mechanism is related to the upstream IGF-1 signalling is still to be investigated. The results of the present study will provide novel data that can be used when developing new approaches to improve the functional condition of denervated SKM cells by sensory protection combined with other enhancing factors
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