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Ivakine E.A.,The Hospital for Sick Children | Cohn R.D.,The Hospital for Sick Children | Cohn R.D.,Center for Genetic Medicine | Cohn R.D.,University of Toronto
Experimental Physiology | Year: 2014

New Findings: What is the topic of this review? This report describes identification and characterization of serum- and glucocorticoid-regulated kinase 1 (SGK1) as a regulator of skeletal muscle mass during hibernation, as well as in physiological and pathophysiological conditions in non-hibernating species. What advances does it highlight? This is first demonstration that SGK1 plays a crucial role in skeletal muscle homeostasis. Overexpression of SGK1 protects mice from immobilization and starvation-induced muscle atrophy. Serum- and glucocorticoid-regulated kinase 1 should be considered as a novel therapeutic target to combat loss of muscle mass in multiple conditions. Muscle disuse and starvation are often associated with a catabolic response leading to a dramatic loss of skeletal muscle mass. Hibernating animals represent a unique situation where muscle mass is maintained despite prolonged periods of immobilization and lack of nutrition. We analysed the molecular pathways upregulated during hibernation in an obligate hibernator, the 13-lined ground squirrel (Ictidomys tridecemlineatus). Although Akt has an established role in skeletal muscle maintenance, we found that activated Akt was decreased in skeletal muscle of hibernating squirrels. Another serine-threonine kinase, serum- and glucocorticoid-regulated kinase 1 (SGK1), was upregulated during hibernation and contributed to protection from loss of muscle mass via downregulation of proteolysis and autophagy and via an increase in protein synthesis. We extended our observations to non-hibernating animals and demonstrated that SGK1-null mice developed muscle atrophy. These mice displayed an exaggerated response to immobilization and starvation. Furthermore, SGK1 overexpression prevented immobilization-induced muscle atrophy. Taken together, our results identify SGK1 as a novel therapeutic target to combat skeletal muscle loss in acquired and inherited forms of muscle atrophy. © 2014 The Physiological Society. Source

Xu R.,Johns Hopkins University | Xu R.,University of Heidelberg | Andres-Mateos E.,Johns Hopkins University | Mejias R.,Johns Hopkins University | And 7 more authors.
Experimental Neurology | Year: 2013

Skeletal muscle atrophy is a very common clinical challenge in many disuse conditions. Maintenance of muscle mass is crucial to combat debilitating functional consequences evoked from these clinical conditions. In contrast, hibernation represents a physiological state in which there is natural protection against disuse atrophy despite prolonged periods of immobilization and lack of nutrient intake.Even though peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1-α (PGC-1α) is a central mediator in muscle remodeling pathways, its role in the preservation of skeletal muscle mass during hibernation remains unclear. Since PGC-1α regulates muscle fiber type formation and mitochondrial biogenesis, we analyzed muscles of 13-lined ground squirrels. We find that animals in torpor exhibit a shift to slow-twitch Type I muscle fibers. This switch is accompanied by activation of the PGC-1α-mediated endurance exercise pathway. In addition, we observe increased antioxidant capacity without evidence of oxidative stress, a marked decline in apoptotic susceptibility, and enhanced mitochondrial abundance and metabolism.These results show that activation of the endurance exercise pathway can be achieved in vivo despite prolonged periods of immobilization, and therefore might be an important mechanism for skeletal muscle preservation during hibernation. This PGC-1α regulated pathway may be a potential therapeutic target promoting skeletal muscle homeostasis and oxidative balance to prevent muscle loss in a variety of inherited and acquired neuromuscular disease conditions. © 2013 Elsevier Inc. Source

MacDonald E.M.,Johns Hopkins University | Andres-Mateos E.,Johns Hopkins University | Mejias R.,Johns Hopkins University | Simmers J.L.,Johns Hopkins University | And 7 more authors.
DMM Disease Models and Mechanisms | Year: 2014

The purpose of our study was to compare two acquired muscle atrophies and the use of myostatin inhibition for their treatment. Myostatin naturally inhibits skeletal muscle growth by binding to ActRIIB, a receptor on the cell surface of myofibers. Because blocking myostatin in an adult wild-type mouse induces profound muscle hypertrophy, we applied a soluble ActRIIB receptor to models of disuse (limb immobilization) and denervation (sciatic nerve resection) atrophy. We found that treatment of immobilized mice with ActRIIB prevented the loss of muscle mass observed in placebo-treated mice. Our results suggest that this protection from disuse atrophy is regulated by serum and glucocorticoid-induced kinase (SGK) rather than by Akt. Denervation atrophy, however, was not protected by ActRIIB treatment, yet resulted in an upregulation of the pro-growth factors Akt, SGK and components of the mTOR pathway. We then treated the denervated mice with the mTOR inhibitor rapamycin and found that, despite a reduction in mTOR activation, there is no alteration of the atrophy phenotype. Additionally, rapamycin prevented the denervation-induced upregulation of the mTORC2 substrates Akt and SGK. Thus, our studies show that denervation atrophy is not only independent from Akt, SGK and mTOR activation but also has a different underlying pathophysiological mechanism than disuse atrophy. Source

Joyce N.C.,University of California at Davis | Hache L.P.,Center for Genetic Medicine | Clemens P.R.,University of Pittsburgh
Physical Medicine and Rehabilitation Clinics of North America | Year: 2012

This article reviews the recent literature regarding bone health as it relates to the patient living with neuromuscular disease (NMD). Studies defining the scope of bone-related disease in NMD are scant. The available evidence is discussed, focusing on abnormal calcium metabolism, increased fracture risk, and the prevalence of both scoliosis and hypovitaminosis D in Duchenne muscular dystrophy, amyotrophic lateral sclerosis, and spinal muscular atrophy. Future directions are discussed, including the urgent need for studies both to determine the nature and extent of poor bone health, and to evaluate the therapeutic effect of available osteoporosis treatments in patients with NMD. © 2012 Elsevier Inc. Source

Pajoohesh-Ganji A.,George Washington University | Knoblach S.M.,Center for Genetic Medicine | Faden A.I.,University of Maryland Baltimore County | Byrnes K.R.,Uniformed Services University of the Health Sciences
Brain Research | Year: 2012

Inflammation has long been implicated in secondary tissue damage after spinal cord injury (SCI). Our previous studies of inflammatory gene expression in rats after SCI revealed two temporally correlated clusters: the first was expressed early after injury and the second was up-regulated later, with peak expression at 1-2 weeks and persistent up-regulation through 6 months. To further address the role of inflammation after SCI, we examined inflammatory genes in a second species, mice, through 28 days after SCI. Using anchor gene clustering analysis, we found similar expression patterns for both the acute and chronic gene clusters previously identified after rat SCI. The acute group returned to normal expression levels by 7 days post injury. The chronic group, which included C1qB, p22phox and galectin-3, showed peak expression at 7 days and remained up-regulated through 28 days. Immunohistochemistry and western blot analysis showed that the protein expression of these genes was consistent with the mRNA expression. Further exploration of the role of one of these genes, galectin-3, suggests that galectin-3 may contribute to secondary injury. In summary, our findings extend our prior gene profiling data by demonstrating the chronic expression of a cluster of microglial associated inflammatory genes after SCI in mice. Moreover, by demonstrating that inhibition of one such factor improves recovery, the findings suggest that such chronic up-regulation of inflammatory processes may contribute to secondary tissue damage after SCI, and that there may be a broader therapeutic window for neuroprotection than generally accepted. © 2012 Elsevier B.V. All rights reserved. Source

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