Nicholas P. Whitehead

University of Washington Seattle, Seattle, Washington, United States

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Publications (6)31.41 Total impact

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    ABSTRACT: Nitric oxide (NO) is a key regulator of skeletal muscle function and metabolism, including vasoregulation, mitochondrial function, glucose uptake, fatigue and excitation-contraction coupling. The main generator of NO in skeletal muscle is the muscle-specific form of neuronal nitric oxide synthase (nNOSμ) produced by the NOS1 gene. Skeletal muscle nNOSμ is predominantly localized at the sarcolemma by interaction with the dystrophin protein complex (DPC). In Duchenne muscular dystrophy (DMD), loss of dystrophin leads to the mislocalization of nNOSμ from the sarcolemma to the cytosol. This perturbation has been shown to impair contractile function and cause muscle fatigue in dystrophic (mdx) mice. Here, we investigated the effect of restoring sarcolemmal nNOSμ on muscle contractile function in mdx mice. To achieve this, we designed a modified form of nNOSμ (NOS-M) that is targeted to the sarcolemma by palmitoylation, even in the absence of the DPC. When expressed specifically in mdx skeletal muscle, NOS-M significantly attenuates force loss due to damaging eccentric contractions and repetitive isometric contractions (fatigue), while also improving force recovery after fatigue. Expression of unmodified nNOSμ at similar levels does not lead to sarcolemmal association and fails to improve muscle function. Aside from the benefits of sarcolemmal-localized NO production, NOS-M also increased the surface membrane levels of utrophin and other DPC proteins, including β-dystroglycan, α-syntrophin and α-dystrobrevin in mdx muscle. These results suggest that the expression of NOS-M in skeletal muscle may be therapeutically beneficial in DMD and other muscle diseases characterized by the loss of nNOSμ from the sarcolemma.
    Human Molecular Genetics 11/2015; DOI:10.1093/hmg/ddv466 · 6.39 Impact Factor
  • M. Kim · D. Rebolledo · N. Whitehead · M. Adams · S. Froehner ·

    Neuromuscular Disorders 10/2015; 25:S290-S291. DOI:10.1016/j.nmd.2015.06.374 · 2.64 Impact Factor
  • N. Whitehead · M. Kim · K. Bible · M. Adams · S. Froehner ·

    Neuromuscular Disorders 10/2015; 25:S315. DOI:10.1016/j.nmd.2015.06.457 · 2.64 Impact Factor
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    Nicholas P. Whitehead · Min Jeong Kim · Kenneth L. Bible · Marvin E. Adams · Stanley C. Froehner ·
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    ABSTRACT: Duchenne muscular dystrophy (DMD) is a lethal, degenerative muscle disease with no effective treatment. DMD muscle pathogenesis is characterized by chronic inflammation, oxidative stress, and fibrosis. Statins, cholesterol-lowering drugs, inhibit these deleterious processes in ischemic diseases affecting skeletal muscle, and therefore have potential to improve DMD. However, statins have not been considered for DMD, or other muscular dystrophies, principally because skeletal-muscle-related symptoms are rare, but widely publicized, side effects of these drugs. Here we show positive effects of statins in dystrophic skeletal muscle. Simvastatin dramatically reduced damage and enhanced muscle function in dystrophic (mdx) mice. Long-term simvastatin treatment vastly improved overall muscle health in mdx mice, reducing plasma creatine kinase activity, an established measure of muscle damage, to near-normal levels. This reduction was accompanied by reduced inflammation, more oxidative muscle fibers, and improved strength of the weak diaphragm muscle. Shorter-term treatment protected against muscle fatigue and increased mdx hindlimb muscle force by 40%, a value comparable to current dystrophin gene-based therapies. Increased force correlated with reduced NADPH Oxidase 2 protein expression, the major source of oxidative stress in dystrophic muscle. Finally, in old mdx mice with severe muscle degeneration, simvastatin enhanced diaphragm force and halved fibrosis, a major cause of functional decline in DMD. These improvements were accompanied by autophagy activation, a recent therapeutic target for DMD, and less oxidative stress. Together, our findings highlight that simvastatin substantially improves the overall health and function of dystrophic skeletal muscles and may provide an unexpected, novel therapy for DMD and related neuromuscular diseases.
    Proceedings of the National Academy of Sciences 09/2015; 112(41):201509536. DOI:10.1073/pnas.1509536112 · 9.67 Impact Factor
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    J M Percival · N P Whitehead · M E Adams · C M Adamo · J.A. Beavo · S C Froehner ·
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    ABSTRACT: Until genetic correction approaches are routinely available for treat-ment of muscular dystrophies, treatments that extend longevity and improve quality of life will be important alternatives. Based on our stud-ies of one isoform of nitric oxide synthase (nNOSb) which localizes on the Golgi with guanylyl cyclase and protein kinase G, we proposed that increasing cGMP levels by inhibition of specific phosphodiesterases (PDEs) would improve cardiac and skeletal muscle function in the mdx mouse. We examined the effect of sildenafil (Viagra), a selective inhibitor of PDE5 which is present in cardiac and diaphragm muscle. Our published results (Adamo et al., 2010, Proc. Natl. Acad. Sci. 107:19079) showed that chronic administration of sildenafil via the drinking water reduces functional deficits in the cardiac performance of aged mdx mice. Furthermore, when sildenafil treatment was started after cardiomyopathy had developed, the established symptoms were reversed within a few days. Chronic administration of sildenafil to mdx mice beginning at 3 weeks of age improved diaphragm function. At 5 months of age, diaphragms from mdx mice treated with sildenafil exhibited less Evans Blue dye uptake and markedly reduced levels of fibrosis, compared to untreated mdx diaphragms. Functional measure-ments showed an increase in specific force. Quantitative PCR analyses of pro-fibrotic and pro-inflammatory gene expression revealed that tran-script levels for TNFa and MMP-13 were upregulated in dystrophic dia-phragm. Sildenafil treatment reduced the transcripts of TNFa and MMP-13 to near normal levels. Our results suggest that sildenafil treat-ment of individuals with muscular dystrophies and other muscle fibrotic diseases may preserve muscle function and integrity.
    Neuromuscular Disorders 10/2012; 22(9-10). DOI:10.1016/j.nmd.2012.06.151 · 2.64 Impact Factor
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    ABSTRACT: Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy caused by mutations in the dystrophin gene. Loss of dystrophin initiates a progressive decline in skeletal muscle integrity and contractile capacity which weakens respiratory muscles including the diaphragm, culminating in respiratory failure, the leading cause of morbidity and mortality in DMD patients. At present, corticosteroid treatment is the primary pharmacological intervention in DMD, but has limited efficacy and adverse side effects. Thus, there is an urgent need for new safe, cost-effective, and rapidly implementable treatments that slow disease progression. One promising new approach is the amplification of nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signalling pathways with phosphodiesterase 5 (PDE5) inhibitors. PDE5 inhibitors serve to amplify NO signalling that is attenuated in many neuromuscular diseases including DMD. We report here that a 14-week treatment of the mdx mouse model of DMD with the PDE5 inhibitor sildenafil (Viagra(®), Revatio(®)) significantly reduced mdx diaphragm muscle weakness without impacting fatigue resistance. In addition to enhancing respiratory muscle contractility, sildenafil also promoted normal extracellular matrix organization. PDE5 inhibition slowed the establishment of mdx diaphragm fibrosis and reduced matrix metalloproteinase-13 (MMP-13) expression. Sildenafil also normalized the expression of the pro-fibrotic (and pro-inflammatory) cytokine tumour necrosis factor α (TNFα). Sildenafil-treated mdx diaphragms accumulated significantly less Evans Blue tracer dye than untreated controls, which is also indicative of improved diaphragm muscle health. We conclude that sildenafil-mediated PDE5 inhibition significantly reduces diaphragm respiratory muscle dysfunction and pathology in the mdx mouse model of Duchenne muscular dystrophy. This study provides new insights into the therapeutic utility of targeting defects in NO-cGMP signalling with PDE5 inhibitors in dystrophin-deficient muscle.
    The Journal of Pathology 09/2012; 228(1):77-87. DOI:10.1002/path.4054 · 7.43 Impact Factor