Abstract
Spinal Cord Injury (SCI) results in severe sub-lesional muscle atrophy and fiber type transformation from slow oxidative to fast glycolytic, both contributing to functional deficits and maladaptive metabolic profiles. Therapeutic countermeasures have had limited success and muscle-related pathology remains a clinical priority. mTOR signaling is known to play a critical role in skeletal muscle growth and metabolism, and signal integration of anabolic and catabolic pathways. Recent studies show that the natural compound ursolic acid (UA) enhances mTOR signaling intermediates, independently inhibiting atrophy and inducing hypertrophy. Here, we examine the effects of UA treatment on sub-lesional muscle mTOR signaling, catabolic genes, and functional deficits following severe SCI in mice. We observe that UA treatment significantly attenuates SCI induced decreases in activated forms of mTOR, and signaling intermediates PI3K, AKT, and S6K, and the upregulation of catabolic genes including FOXO1, MAFbx, MURF-1, and PSMD11. In addition, UA treatment improves SCI induced deficits in body and sub-lesional muscle mass, as well as functional outcomes related to muscle function, motor coordination, and strength. These findings provide evidence that UA treatment may be a potential therapeutic strategy to improve muscle-specific pathological consequences of SCI.
Highlights
In spinal cord injury (SCI), a reduction in anabolic hormones such as testosterone, insulin and insulin-like growth factor-1 (IGF-1) [45, 46] may contribute to reduced IGF-1 receptor activation of metabolically-linked signaling pathways in muscle. It is well-established that activation of phosphoinositide-3 kinase (PI3K)/Akt and downstream anabolic target mammalian target of rapamycin regulate, in part, skeletal muscle protein synthesis, cell growth and metabolism. [47,48,49] mTOR-activation regulates the transcription factor fork-head box protein 01 (FOXO1), which is associated with catabolic genes involved with ubiquitin-proteasomal degradation in muscle. [50] mTOR is a complex signal integrator that regulates both anabolic and catabolic processes in the muscle, these processes are not well defined in SCI
To define whether SCI alters activation of IGF-1/mTOR signaling cascades, and examine the effect of ursolic acid (UA) treatment, soleus muscle lysates from control and injured animals at various times after trauma were analyzed by immunoblotting procedures (Fig 1)
In mice treated with UA, changes in expression of activated forms of all proteins examined were no longer significant at 1-week post-SCI compared to sham
Summary
Traumatic spinal cord injury (SCI) incites numerous pathophysiological changes and persistent metabolic abnormalities [1,2,3,4,5] that contribute to long-term effects on body systems. In SCI, a reduction in anabolic hormones such as testosterone, insulin and insulin-like growth factor-1 (IGF-1) [45, 46] may contribute to reduced IGF-1 receptor activation of metabolically-linked signaling pathways in muscle. It is well-established that activation of phosphoinositide-3 kinase (PI3K)/Akt and downstream anabolic target mammalian target of rapamycin (mTOR) regulate, in part, skeletal muscle protein synthesis, cell growth and metabolism. It is well-established that activation of phosphoinositide-3 kinase (PI3K)/Akt and downstream anabolic target mammalian target of rapamycin (mTOR) regulate, in part, skeletal muscle protein synthesis, cell growth and metabolism. [47,48,49] mTOR-activation regulates the transcription factor fork-head box protein 01 (FOXO1), which is associated with catabolic genes involved with ubiquitin-proteasomal degradation in muscle. [50] mTOR is a complex signal integrator that regulates both anabolic and catabolic processes in the muscle, these processes are not well defined in SCI
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