Metabolic remodeling agents show beneficial effects in the dystrophin- deficient mdx mouse model

Jahnke, Vanessa E.; Meulen, J. H. van der; Johnston, Helen; Ghimbovschi, Svetlana; Partridge, T.; Hoffman, Eric P.; Nagaraju, Kanneboyina

doi:10.1186/2044-5040-2-16

Cited by 80 publications

(86 citation statements)

References 45 publications

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“…There is increasing interest in using AMPK activation as a therapeutic strategy to improve muscle pathology in DMD. Chronic activation of AMPK with administration of the AMP analog 5-aminoimidazole-4-carboxamide riboside (AICAR) (47) in mdx mice has been shown to promote a slow oxidative muscle phenotype, increase utrophin expression, and enhance sarcolemmal stability in skeletal muscle (48), and to reduce ongoing muscle damage and increase skeletal muscle strength (49,50). Whether any of these effects depends on increased NO production, and whether AMPK activation can enhance NO production in the dystrophic heart, are unclear.…”

Section: Stretch-induced Nnos Phosphorylation Is Impaired In Dystrophin-mentioning

confidence: 99%

Dystrophin–glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling

Garbincius

Michele

2015

Proc. Natl. Acad. Sci. U.S.A.

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Patients deficient in dystrophin, a protein that links the cytoskeleton to the extracellular matrix via the dystrophin-glycoprotein complex (DGC), exhibit muscular dystrophy, cardiomyopathy, and impaired muscle nitric oxide (NO) production. We used live-cell NO imaging and in vitro cyclic stretch of isolated adult mouse cardiomyocytes as a model system to investigate if and how the DGC directly regulates the mechanical activation of muscle NO signaling. Acute activation of NO synthesis by mechanical stretch was impaired in dystrophin-deficient mdx cardiomyocytes, accompanied by loss of stretch-induced neuronal NO synthase (nNOS) S1412 phosphorylation. Intriguingly, stretch induced the acute activation of AMP-activated protein kinase (AMPK) in normal cardiomyocytes but not in mdx cardiomyocytes, and specific inhibition of AMPK was sufficient to attenuate mechanoactivation of NO production. Therefore, we tested whether direct pharmacologic activation of AMPK could bypass defective mechanical signaling to restore nNOS activity in dystrophin-deficient cardiomyocytes. Indeed, activation of AMPK with 5-aminoimidazole-4-carboxamide riboside or salicylate increased nNOS S1412 phosphorylation and was sufficient to enhance NO production in mdx cardiomyocytes. We conclude that the DGC promotes the mechanical activation of cardiac nNOS by acting as a mechanosensor to regulate AMPK activity, and that pharmacologic AMPK activation may be a suitable therapeutic strategy for restoring nNOS activity in dystrophin-deficient hearts and muscle.T he muscular dystrophies are a group of muscle wasting disorders characterized by progressive weakening and degeneration of striated muscle. The most common form is Duchenne muscular dystrophy (DMD), an X-linked disorder caused by genetic disruption of dystrophin (1) that affects 1 in 3,500-5,000 males (2, 3). DMD and several other types of muscular dystrophy result from disruption of the dystrophin-glycoprotein complex (DGC), a structure that spans the sarcolemma and forms a mechanical linkage between the cytoskeleton and the extracellular matrix via the association of dystrophin with subsarcolemmal γ-actin and the binding of α-dystroglycan to laminin (4). The generally accepted role for this complex is to act as a molecular shock absorber and stabilize the plasma membrane during muscle contraction. Disruption of the DGC's linkage between the cytoskeleton and extracellular matrix, such as occurs in DMD (1, 5-7) or with the disruption of α-dystroglycan-laminin binding in glycosylation-deficient muscular dystrophies (8, 9), leads to destabilization of the plasma membrane, rendering skeletal muscle fibers and cardiomyocytes susceptible to stretch-or contraction-induced injury and cell death (10)(11)(12)(13)(14).In addition to this structural role, a signaling function for the DGC has been proposed based on its association with several signaling proteins including Grb2-Sos1 (15), MEK and ERK (16), heterotrimeric G protein subunits (17, 18), archvillin (19), and neuronal nitric oxide synthase (n...

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Section: Stretch-induced Nnos Phosphorylation Is Impaired In Dystrophin-mentioning

confidence: 99%

Dystrophin–glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling

Garbincius

Michele

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…This form of muscle plasticity is often accompanied by increases in utrophin A expression, which is of great importance in the DMD context (31,36,43). We thus first examined by Western blot expression of utrophin A in muscles from the three groups of animals.…”

Section: Rsv-mdsd Induces Sirt1 and Pgc-1␣ Signaling Andmentioning

confidence: 99%

“…For over a decade, our laboratory has advanced the hypothesis that promotion of the slow, oxidative myogenic program confers molecular and physiological benefits in dystrophic skeletal muscle (21,36,37). Subsequent and parallel work of others has further solidified this theory (2,5,6,17,26,31,40,57). Studies aimed at deciphering the mechanisms involved in controlling the slow, oxidative phenotype in dystrophic skeletal muscle are important as they pave the way for target identification and rational design of specific interventions focused on ameliorating the pathology of DMD via pharmacological agents.…”

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confidence: 99%

Resveratrol induces expression of the slow, oxidative phenotype in mdx mouse muscle together with enhanced activity of the SIRT1-PGC-1α axis

Ljubicic

Burt

Lunde

et al. 2014

American Journal of Physiology-Cell Physiology

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Ljubicic V, Burt M, Lunde JA, Jasmin BJ. Resveratrol induces expression of the slow, oxidative phenotype in mdx mouse muscle together with enhanced activity of the SIRT1-PGC-1␣ axis. Am J Physiol Cell Physiol 307: C66 -C82, 2014. First published April 24, 2014; doi:10.1152/ajpcell.00357.2013.-Slower, more oxidative muscle fibers are more resistant to the dystrophic pathology in Duchenne muscular dystrophy (DMD) patients as well as in the preclinical mdx mouse model of DMD. Therefore, one therapeutic strategy for DMD focuses on promoting expression of the slow, oxidative myogenic program. In the current study, we explored the therapeutic potential of stimulating the slow, oxidative phenotype in mdx mice by feeding 6-wk-old animals with the natural phenol resveratrol (RSV; ϳ100 mg·kg Ϫ1 ·day Ϫ1 ) for 6 wk. Sirtuin 1 (SIRT1) activity and protein levels increased significantly, as well as peroxisome proliferatoractivated receptor-␥ coactivator-1␣ (PGC-1␣) activity, in the absence of alterations in AMPK signaling. These adaptations occurred concomitant with evidence of a fast, glycolytic, to slower, more oxidative fiber type conversion, including mitochondrial biogenesis and increased expression of slower myosin heavy chain isoforms. These positive findings raised the question of whether increased exposure to RSV would result in greater therapeutic benefits. We discovered that an elevated RSV dose of ϳ500 mg·kg Ϫ1 ·day Ϫ1 across a duration of 12 wk was clearly less effective at muscle remodeling in mdx mice. This treatment protocol failed to influence SIRT1 or AMPK signaling and did not result in a shift towards a slower, more oxidative phenotype. Taken together, this study demonstrates that RSV can stimulate SIRT1 and PGC-1␣ activation, which in turn may promote expression of the slow, oxidative myogenic program in mdx mouse muscle. The data also highlight the importance of selecting an appropriate dosage regimen of RSV to maximize its potential therapeutic effectiveness for future application in DMD patients. DMD; SIRT1; utrophin A; PGC-1␣; AMPK DUCHENNE MUSCULAR DYSTROPHY (DMD) is a life-limiting, progressive muscle wasting disease that causes the loss of muscle function and independence. Genetic disruption of the dystrophin gene prevents the synthesis of the full-length dystrophin protein in skeletal muscle, which is the primary cause of the pathology (53). In the absence of dystrophin, the recruitment of the dystrophin-associated protein complex to the sarcolemma is impaired thereby creating a pathophysiological cascade with numerous adverse downstream events, including compromised sarcolemmal integrity, increased intracellular calcium, defective mitochondrial morphology, myofibrillar degradation, and ultimately death of the fibers (12). Over time, repeated cycles of muscle degeneration/regeneration result in the exhaustion of the muscle progenitor pool and the failure of regenerative capacity. Multiple experimental approaches to treat DMD are currently under investigation, including exon skipping and stop codo...

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“…Increased fatty acid oxidation and oxygen consumption, IIb-to-IIx myosin isoform shift, enhanced aerobic capacity and running endurance have been reported after AICAR administration to experimental animals (46) . AICAR-induced AMPK activation improves muscle phenotype in dystrophic mdx mice by activating autophagy (53) . The same drug reverts angiotensin II-induced muscle wasting, down-regulating the induction of the muscle-specific ubiquitin ligases and improving PGC-1α expression (65) .…”

Section: Drugs Mimicking Exercisementioning

confidence: 99%

“…GW501516 treatment improves muscle dystrophy by down-regulating inflammationdependent pathways (53) . The same drug attenuates metabolic abnormalities and improves muscle phenotype in experimental models of cardiovascular disease (48) .…”

Section: Drugs Mimicking Exercisementioning

confidence: 99%

Novel investigational drugs mimicking exercise for the treatment of cachexia

Penna

Ballarò

et al. 2015

Expert Opinion on Investigational Drugs

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Introduction: Cachexia is a syndrome characterized by body weight loss, muscle wasting, and metabolic abnormalities, that frequently complicates the management of people affected by chronic diseases. No effective therapy is actually available, although several drugs are under clinical evaluation. Altered energy metabolism markedly contributes to the pathogenesis of cachexia; it can be improved by exercise, able to both induce anabolism and inhibit catabolism.Areas covered in this review: This review will focus on exercise mimetics and on their potential inclusion in combined protocols to treat cachexia, with particular reference to the cancer-associated one.Expert opinion: Despite exercise improves muscle phenotype, most patients retain sedentary habits quite difficult to disrupt. Moreover, they frequently present with chronic fatigue and co-morbidities that reduce exercise tolerance. For these reasons drugs mimicking exercise could be beneficial also in the absence of patient compliance to the practice of physical activity. Different exercise mimetics are now available and, yet some of them may exert serious side-effects, investigating their effectiveness on muscle phenotype will provide a new tool for the management of cachexia.4

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Metabolic remodeling agents show beneficial effects in the dystrophin- deficient mdx mouse model

Cited by 80 publications

References 45 publications

Dystrophin–glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling

Dystrophin–glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling

Resveratrol induces expression of the slow, oxidative phenotype in mdx mouse muscle together with enhanced activity of the SIRT1-PGC-1α axis

Novel investigational drugs mimicking exercise for the treatment of cachexia

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