Person: Widrick, Jeffrey
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Widrick
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Jeffrey
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Widrick, Jeffrey
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Publication Concurrent muscle and bone deterioration in a murine model of cancer cachexia(Blackwell Publishing Ltd, 2013) Choi, EunHi; Carruthers, Kadir; Zhang, Li; Thomas, Nathan; Battaglino, Ricardo A; Morse, Leslie R.; Widrick, JeffreyCachexia is defined as an excessive, involuntary loss of fat and lean tissue. We tested the validity of the Lewis lung carcinoma (LLC) as a model of cancer cachexia and examined its effect on the two major lean tissue components, skeletal muscle and bone. LLC cells (0.75 × 106) were injected into the left thigh of C57BL/6 mice. Control mice received an equal volume injection of growth media. Tumors were observed in all LLC-injected animals 21 and 25 days post inoculation. LLC-injected animals showed significant reductions in fat and lean mass despite having the same average daily caloric intake as media-treated mice. Global bone mineral density (BMD) had fallen by 5% and 6% in the LLC animals at 21 and 25 days, respectively, compared to a BMD increase of 5% in the 25-day media-treated animals. Extensor digitorum longus (EDL) muscles (isolated from the noninjected hindlimb) showed earlier and quantitatively greater losses in mass, physiological cross-sectional area (pCSA), and tetanic force compared to soleus muscles from the same hindlimb. By the 25th day post-LLC inoculation, EDL force/pCSA was reduced by 19% versus media treatment. This loss in specific force was not trivial as it accounted for about one-third of the reduction in EDL absolute force at this time point. Muscle strips dissected from the diaphragm of LLC mice also exhibited significant reductions in force/pCSA at day 25. We conclude that LLC is a valid model of cachexia that induces rapid losses in global BMD and in limb and respiratory muscle function.Publication Whole Body Periodic Acceleration Is an Effective Therapy to Ameliorate Muscular Dystrophy in mdx Mice(Public Library of Science, 2014) Altamirano, Francisco; Perez, Claudio; Liu, Min; Widrick, Jeffrey; Barton, Elisabeth R.; Allen, Paul; Adams, Jose A.; Lopez, Jose R.Duchenne muscular dystrophy (DMD) is a genetic disorder caused by the absence of dystrophin in both skeletal and cardiac muscles. This leads to severe muscle degeneration, and dilated cardiomyopathy that produces patient death, which in most cases occurs before the end of the second decade. Several lines of evidence have shown that modulators of nitric oxide (NO) pathway can improve skeletal muscle and cardiac function in the mdx mouse, a mouse model for DMD. Whole body periodic acceleration (pGz) is produced by applying sinusoidal motion to supine humans and in standing conscious rodents in a headward-footward direction using a motion platform. It adds small pulses as a function of movement frequency to the circulation thereby increasing pulsatile shear stress to the vascular endothelium, which in turn increases production of NO. In this study, we examined the potential therapeutic properties of pGz for the treatment of skeletal muscle pathology observed in the mdx mouse. We found that pGz (480 cpm, 8 days, 1 hr per day) decreased intracellular Ca2+ and Na+ overload, diminished serum levels of creatine kinase (CK) and reduced intracellular accumulation of Evans Blue. Furthermore, pGz increased muscle force generation and expression of both utrophin and the carboxy-terminal PDZ ligand of nNOS (CAPON). Likewise, pGz (120 cpm, 12 h) applied in vitro to skeletal muscle myotubes reduced Ca2+ and Na+ overload, diminished abnormal sarcolemmal Ca2+ entry and increased phosphorylation of endothelial NOS. Overall, this study provides new insights into the potential therapeutic efficacy of pGz as a non-invasive and non-pharmacological approach for the treatment of DMD patients through activation of the NO pathway.Publication Evaluation of Electrical Impedance as a Biomarker of Myostatin Inhibition in Wild Type and Muscular Dystrophy Mice(Public Library of Science, 2015) Sanchez, Benjamin; Li, Jia; Yim, Sung; Pacheck, Adam; Widrick, Jeffrey; Rutkove, SewardObjectives: Non-invasive and effort independent biomarkers are needed to better assess the effects of drug therapy on healthy muscle and that affected by muscular dystrophy (mdx). Here we evaluated the use of multi-frequency electrical impedance for this purpose with comparison to force and histological parameters. Methods: Eight wild-type (wt) and 10 mdx mice were treated weekly with RAP-031 activin type IIB receptor at a dose of 10 mg kg−1 twice weekly for 16 weeks; the investigators were blinded to treatment and disease status. At the completion of treatment, impedance measurements, in situ force measurements, and histology analyses were performed. Results: As compared to untreated animals, RAP-031 wt and mdx treated mice had greater body mass (18% and 17%, p < 0.001 respectively) and muscle mass (25% p < 0.05 and 22% p < 0.001, respectively). The Cole impedance parameters in treated wt mice, showed a 24% lower central frequency (p < 0.05) and 19% higher resistance ratio (p < 0.05); no significant differences were observed in the mdx mice. These differences were consistent with those seen in maximum isometric force, which was greater in the wt animals (p < 0.05 at > 70 Hz), but not in the mdx animals. In contrast, maximum force normalized by muscle mass was unchanged in the wt animals and lower in the mdx animals by 21% (p < 0.01). Similarly, myofiber size was only non-significantly higher in treated versus untreated animals (8% p = 0.44 and 12% p = 0.31 for wt and mdx animals, respectively). Conclusions: Our findings demonstrate electrical impedance of muscle reproduce the functional and histological changes associated with myostatin pathway inhibition and do not reflect differences in muscle size or volume. This technique deserves further study in both animal and human therapeutic trials.Publication RNA helicase, DDX27 regulates skeletal muscle growth and regeneration by modulation of translational processes(Public Library of Science, 2018) Bennett, Alexis H.; O’Donohue, Marie-Francoise; Gundry, Stacey R.; Chan, Aye T.; Widrick, Jeffrey; Draper, Isabelle; Chakraborty, Anirban; Zhou, Yi; Zon, Leonard; Gleizes, Pierre-Emmanuel; Beggs, Alan; Gupta, VandanaGene expression in a tissue-specific context depends on the combined efforts of epigenetic, transcriptional and post-transcriptional processes that lead to the production of specific proteins that are important determinants of cellular identity. Ribosomes are a central component of the protein biosynthesis machinery in cells; however, their regulatory roles in the translational control of gene expression in skeletal muscle remain to be defined. In a genetic screen to identify critical regulators of myogenesis, we identified a DEAD-Box RNA helicase, DDX27, that is required for skeletal muscle growth and regeneration. We demonstrate that DDX27 regulates ribosomal RNA (rRNA) maturation, and thereby the ribosome biogenesis and the translation of specific transcripts during myogenesis. These findings provide insight into the translational regulation of gene expression in myogenesis and suggest novel functions for ribosomes in regulating gene expression in skeletal muscles.Publication In Vivo Gene Editing in Dystrophic Mouse Muscle and Muscle Stem Cells(American Association for the Advancement of Science (AAAS), 2016-01-22) Tabebordbar, Mohammadsharif; Zhu, Kexian; Cheng, Jason K. W.; Chew, Wei Leong; Widrick, Jeffrey; Yan, Winston; Maesner, Claire; Wu, Elizabeth Y.; Xiao, Ru; Ran, F. Ann; Cong, Le; Zhang, Feng; Vandenberghe, Luk; Church, George; Wagers, AmyFrame-disrupting mutations in the DMD gene, encoding dystrophin, compromise myofiber integrity and drive muscle deterioration in Duchenne muscular dystrophy (DMD). Removing one or more exons from the mutated transcript can produce an in-frame mRNA and a truncated but still functional protein. In this study, we develop and test a direct gene editing approach to induce exon deletion and recover dystrophin expression in the mdx mouse model of DMD. Delivery by adeno-associated virus (AAV) of clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 endonucleases coupled with paired guide RNAs flanking the mutated Dmd exon23 resulted in excision of intervening DNA and restored Dystrophin reading frame in myofibers, cardiomyocytes and muscle stem cells following local or systemic delivery. AAV-Dmd CRISPR-treatment partially recovered muscle functional deficiencies and generated a pool of endogenously corrected myogenic precursors in mdx mouse muscle.