Risk Factors, Clinical Features, and Polygenic Risk Scores in Schizophrenia and Schizoaffective Disorder Depressive-Type

There is controversy about the status of schizoaffective disorder depressive-type (SA-D), particularly whether it should be considered a form of schizophrenia or a distinct disorder. We aimed to determine whether individuals with SA-D differ from individuals with schizophrenia in terms of demographic, premorbid, and lifetime clinical characteristics, and genetic liability to schizophrenia, depression, and bipolar disorder. Participants were from the CardiffCOGS sample and met ICD-10 criteria for schizophrenia (n = 713) or SA-D (n = 151). Two samples, Cardiff Affected-sib (n = 354) and Cardiff F-series (n = 524), were used for replication. For all samples, phenotypic data were ascertained through structured interview, review of medical records, and an ICD-10 diagnosis made by trained researchers. Univariable and multivariable logistic regression models were used to compare individuals with schizophrenia and SA-D for demographic and clinical characteristics, and polygenic risk scores (PRS). In the CardiffCOGS, SA-D, compared to schizophrenia, was associated with female sex, childhood abuse, history of alcohol dependence, higher functioning Global Assessment Scale (GAS) score in worst episode of psychosis, lower functioning GAS score in worst episode of depression, and reduced lifetime severity of disorganized symptoms. Individuals with SA-D had higher depression PRS compared to those with schizophrenia. PRS for schizophrenia and bipolar disorder did not significantly differ between SA-D and schizophrenia. Compared to individuals with schizophrenia, individuals with SA-D had higher rates of environmental and genetic risk factors for depression and a similar genetic liability to schizophrenia. These findings are consistent with SA-D being a sub-type of schizophrenia resulting from elevated liability to both schizophrenia and depression

Quantification of the Frequency and Multiplicity of Infection of Respiratory- and Lymph Node–Resident Dendritic Cells During Influenza Virus Infection

Background: Previous studies have demonstrated that DC differentially regulate influenza A virus (IAV)–specific CD8 T cell responses in vivo during high and low dose IAV infections. Furthermore, in vitro infection of DC with IAV at low versus high multiplicities of infection (MOI) results in altered cytokine production and a reduced ability to prime naïve CD8 T cell responses. Flow cytometric detection of IAV proteins within DC, a commonly used method for detection of cellular IAV infection, does not distinguish between the direct infection of these cells or their uptake of viral proteins from dying epithelial cells. Methods/Principal Findings: We have developed a novel, sensitive, single-cell RT-PCR–based approach to assess the infection of respiratory DC (rDC) and lymph node (LN)-resident DC (LNDC) following high and low dose IAV infections. Our results show that, while a fraction of both rDC and LNDC contain viral mRNA following IAV infection, there is little correlation between the percentage of rDC containing viral mRNA and the initial IAV inoculum dose. Instead, increasing IAV inoculums correlate with augmented rDC MOI. Conclusion/Significance: Together, our results demonstrate a novel and sensitive method for the detection of direct IAV infection at the single-cell level and suggest that the previously described ability of DC to differentially regulate IAV-specific T cell responses during high and low dose IAV infections could relate to the MOI of rDC within the LN rather than th

A self-report risk index to predict occurrence of dementia in three independent cohorts of older adults: The ANU-ADRI

Background and Aims: The Australian National University AD Risk Index (ANU-ADRI, http://anuadri.anu.edu.au) is a self-report risk index developed using an evidence-based medicine approach to measure risk of Alzheimer's disease (AD). We aimed to evaluate the extent to which the ANU-ADRI can predict the risk of AD in older adults and to compare the ANU-ADRI to the dementia risk index developed from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study for middle-aged cohorts. Methods: This study included three validation cohorts, i.e., the Rush Memory and Aging Study (MAP) (n = 903, age ≥53 years), the Kungsholmen Project (KP) (n = 905, age ≥75 years), and the Cardiovascular Health Cognition Study (CVHS) (n = 2496, age ≥65 years) that were each followed for dementia. Baseline data were collected on exposure to the 15 risk factors included in the ANU-ADRI of which MAP had 10, KP had 8 and CVHS had 9. Risk scores and C-statistics were computed for individual participants for the ANU-ADRI and the CAIDE index. Results: For the ANU-ADRI using available data, the MAP study c-statistic was 0.637 (95% CI 0.596-0.678), for the KP study it was 0.740 (0.712-0.768) and for the CVHS it was 0.733 (0.691-0.776) for predicting AD. When a common set of risk and protective factors were used c-statistics were 0.689 (95% CI 0.650-0.727), 0.666 (0.628-0.704) and 0.734 (0.707-0.761) for MAP, KP and CVHS respectively. Results for CAIDE ranged from c-statistics of 0.488 (0.427-0.554) to 0.595 (0.565-0.625). Conclusion: A composite risk score derived from the ANU-ADRI weights including 8-10 risk or protective factors is a valid, self-report tool to identify those at risk of AD and dementia. The accuracy can be further improved in studies including more risk factors and younger cohorts with long-term follow-up. © 2014 Anstey et al

Investigating the genetic architecture of general and specific psychopathology in adolescence

Whilst associations between polygenic risk scores (PRSs) for schizophrenia and various phenotypic outcomes have been reported, an understanding of developmental pathways can only be gained by modelling comorbidity across psychopathology. We examine how genetic risk for schizophrenia relates to adolescent psychosis-related and internalizing psychopathology using a latent modelling approach, and compare this to genetic risk for other psychiatric disorders, to gain a more comprehensive understanding of the developmental pathways at this age. PRSs for schizophrenia, major depressive disorder, neuroticism and bipolar disorder were generated for individuals in the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Multivariate linear regression was used to examine the relationships of these PRSs with psychopathology factors modelled within (i) a correlated factors structure and (ii) a bifactor structure. The schizophrenia PRS was associated with an increase in factors describing psychotic experiences, negative dimension, depression and anxiety, but, when modelling a general psychopathology factor based on these measures, specific effects above this persisted only for the negative dimension. Similar factor relationships were observed for the neuroticism PRS, with a (weak) specific effect only for anxiety once modelling general psychopathology. Psychopathology during adolescence can be described by a general psychopathology construct that captures common variance as well as by specific constructs capturing remaining non-shared variance. Schizophrenia risk genetic variants identified through genome-wide association studies mainly index negative rather than positive symptom psychopathology during adolescence. This has potentially important implications both for research and risk prediction in high-risk samples

Inhibitory Receptors Are Expressed by Trypanosoma cruzi-Specific Effector T Cells and in Hearts of Subjects with Chronic Chagas Disease

We had formerly demonstrated that subjects chronically infected with Trypanosoma cruzi show impaired T cell responses closely linked with a process of T cell exhaustion. Recently, the expression of several inhibitory receptors has been associated with T cell dysfunction and exhaustion. In this study, we have examined the expression of the cytotoxic T lymphocyte antigen 4 (CTLA-4) and the leukocyte immunoglobulin like receptor 1 (LIR-1) by peripheral T. cruzi antigen-responsive IFN-gamma (IFN-γ)-producing and total T cells from chronically T. cruzi-infected subjects with different clinical forms of the disease. CTAL-4 expression was also evaluated in heart tissue sections from subjects with severe myocarditis. The majority of IFN-γ-producing CD4+ T cells responsive to a parasite lysate preparation were found to express CTLA-4 but considerably lower frequencies express LIR-1, irrespective of the clinical status of the donor. Conversely, few IFN-γ-producing T cells responsive to tetanus and diphtheria toxoids expressed CTLA-4 and LIR-1. Polyclonal stimulation with anti-CD3 antibodies induced higher frequencies of CD4+CTAL-4+ T cells in patients with severe heart disease than in asymptomatic subjects. Ligation of CTLA-4 and LIR-1 with their agonistic antibodies, in vitro, reduces IFN-γ production. Conversely, CTLA-4 blockade did not improved IFN-γ production in response to T. cruzi antigens. Subjects with chronic T. cruzi infection had increased numbers of CD4+LIR-1+ among total peripheral blood mononuclear cells, relative to uninfected individuals and these numbers decreased after treatment with benznidazole. CTLA-4 was also expressed by CD3+ T lymphocytes infiltrating heart tissues from chronically infected subjects with severe myocarditis. These findings support the conclusion that persistent infection with T. cruzi leads to the upregulation of inhibitory receptors which could alter parasite specific T cell responses in the chronic phase of Chagas disease

Activated Met Signalling in the Developing Mouse Heart Leads to Cardiac Disease

BACKGROUND: The Hepatocyte Growth Factor (HGF) is a pleiotropic cytokine involved in many physiological processes, including skeletal muscle, placenta and liver development. Little is known about its role and that of Met tyrosine kinase receptor in cardiac development. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we generated two transgenic mice with cardiac-specific, tetracycline-suppressible expression of either Hepatocyte Growth Factor (HGF) or the constitutively activated Tpr-Met kinase to explore: i) the effect of stimulation of the endogenous Met receptor by autocrine production of HGF and ii) the consequence of sustained activation of Met signalling in the heart. We first showed that Met is present in the neonatal cardiomyocytes and is responsive to exogenous HGF. Exogenous HGF starting from prenatal stage enhanced cardiac proliferation and reduced sarcomeric proteins and Connexin43 (Cx43) in newborn mice. As adults, these transgenics developed systolic contractile dysfunction. Conversely, prenatal Tpr-Met expression was lethal after birth. Inducing Tpr-Met expression during postnatal life caused early-onset heart failure, characterized by decreased Cx43, upregulation of fetal genes and hypertrophy. CONCLUSIONS/SIGNIFICANCE: Taken together, our data show that excessive activation of the HGF/Met system in development may result in cardiac damage and suggest that Met signalling may be implicated in the pathogenesis of cardiac disease

Regulation of Lipogenesis by Glucocorticoids and Insulin in Human Adipose Tissue

Patients with glucocorticoid (GC) excess, Cushing's syndrome, develop a classic phenotype characterized by central obesity and insulin resistance. GCs are known to increase the release of fatty acids from adipose, by stimulating lipolysis, however, the impact of GCs on the processes that regulate lipid accumulation has not been explored. Intracellular levels of active GC are dependent upon the activity of 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) and we have hypothesized that 11β-HSD1 activity can regulate lipid homeostasis in human adipose tissue (Chub-S7 cell line and primary cultures of human subcutaneous (sc) and omental (om) adipocytes. Across adipocyte differentiation, lipogenesis increased whilst β-oxidation decreased. GC treatment decreased lipogenesis but did not alter rates of β-oxidation in Chub-S7 cells, whilst insulin increased lipogenesis in all adipocyte cell models. Low dose Dexamethasone pre-treatment (5 nM) of Chub-S7 cells augmented the ability of insulin to stimulate lipogenesis and there was no evidence of adipose tissue insulin resistance in primary sc cells. Both cortisol and cortisone decreased lipogenesis; selective 11β-HSD1 inhibition completely abolished cortisone-mediated repression of lipogenesis. GCs have potent actions upon lipid homeostasis and these effects are dependent upon interactions with insulin. These in vitro data suggest that manipulation of GC availability through selective 11β-HSD1 inhibition modifies lipid homeostasis in human adipocytes

Zinc uptake promotes myoblast differentiation via Zip7 transporter and activation of Akt signalling transduction pathway

[EN] Myogenic regeneration occurs through a chain of events beginning with the output of satellite cells from quiescent state, formation of competent myoblasts and later fusion and differentiation into myofibres. Traditionally, growth factors are used to stimulate muscle regeneration but this involves serious off-target effects, including alterations in cell homeostasis and cancer. In this work, we have studied the use of zinc to trigger myogenic differentiation. We show that zinc promotes myoblast proliferation, differentiation and maturation of myofibres. We demonstrate that this process occurs through the PI3K/Akt pathway, via zinc stimulation of transporter Zip7. Depletion of zinc transporter Zip7 by RNA interference shows reduction of both PI3K/Akt signalling and a significant reduction of multinucleated myofibres and myotubes development. Moreover, we show that mature myofibres, obtained through stimulation with high concentrations of zinc, accumulate zinc and so we hypothesise their function as zinc reservoirs into the cell.P.R. and R.S. acknowledges support from the Spanish Ministry of Economy and Competitiveness (MINECO) (MAT2015-69315-C3-1-R). P.R. acknowledges the Fondo Europeo de Desarrollo Regional (FEDER). CIBER-BBN is an initiative funded by the VI National R&D&I Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. R.S. acknowledges the support from the Spanish MECD through the PRX16/00208 grant. MSS acknowledges support from the European Research Council (ERC - HealInSynergy 306990) and the UK Engineering and Physical Sciences Research Council (EPSRC - EP/P001114/1)Mnatsakanyan, H.; Sabater I Serra, R.; Rico Tortosa, PM.; Salmerón Sánchez, M. (2018). Zinc uptake promotes myoblast differentiation via Zip7 transporter and activation of Akt signalling transduction pathway. Scientific Reports. 8:1-14. https://doi.org/10.1038/s41598-018-32067-0S1148Frontera, W. R. & Ochala, J. Skeletal muscle: a brief review of structure and function. Calcif. Tissue Int. 96, 183–195 (2015).Wolfe, R. R., Frontera, W. R. & Ochala, J. The underappreciated role of muscle in health and disease. Am. J. Clin. Nutr. 84, 475–82 (2006).Sciorati, C., Rigamonti, E., Manfredi, A. A. & Rovere-Querini, P. Cell death, clearance and immunity in the skeletal muscle. Cell Death Differ. 23, 927–937 (2016).Wang, Y. X. & Rudnicki, M. A. Satellite cells, the engines of muscle repair. Nat. Rev. Mol. Cell Biol. 13, 127–133 (2011).Yin, H., Price, F. & Rudnicki, M. A. Satellite cells and the muscle stem cell niche. Physiol. Rev. 93, 23–67 (2013).Dhawan, J. & Rando, T. A. Stem cells in postnatal myogenesis: Molecular mechanisms of satellite cell quiescence, activation and replenishment. Trends Cell Biol. 15, 666–673 (2005).Yun, K. & Wold, B. Skeletal muscle determination and differentiation: Story of a core regulatory network and its context. Curr. Opin. Cell Biol. 8, 877–889 (1996).Gharaibeh, B. et al. Biological approaches to improve skeletal muscle healing after injury and disease. Birth Defects Res. Part C Embryo Today Rev. 96, 82–94 (2012).Schiaffino, S. & Mammucari, C. Regulation of skeletal muscle growth by the IGF1-Akt/PKB pathway: insights from genetic models. Skelet. Muscle 1, 4 (2011).Sandri, M. Signaling in muscle atrophy and hypertrophy. Physiology (Bethesda). 23, 160–70 (2008).Karalaki, M., Fili, S., Philippou, A. & Koutsilieris, M. Muscle regeneration: cellular and molecular events. In Vivo 23, 779–96 (2009).Fujio, Y. et al. Cell cycle withdrawal promotes myogenic induction of Akt, a positive modulator of myocyte survival. Mol. Cell. Biol. 19, 5073–82 (1999).Wilson, E. M. & Rotwein, P. Control of MyoD function during initiation of muscle differentiation by an autocrine signaling pathway activated by insulin-like growth factor-II. J. Biol. Chem. 281, 29962–29971 (2006).Sun, L., Liu, L., Yang, X. & Wu, Z. Akt binds prohibitin 2 and relieves its repression of MyoD and muscle differentiation. J. Cell Sci. 117, 3021–3029 (2004).Milner, D. & Cameron, J. Muscle repair and regeneration: stem cells, scaffolds, and the contributions of skeletal muscle to amphibian limb regeneration. Curr. Top. Microbiol. Immunol. 367, 133–159 (2013).Liu, C. et al. PI3K/Akt signaling transduction pathway is involved in rat vascular smooth muscle cell proliferation induced by apelin-13. Acta Biochim Biophys Sin 42, 396–402 (2010).Eriksson, M., Taskinen, M. & Leppä, S. Mitogen Activated Protein Kinase-Dependent Activation of c-Jun and c-Fos is required for Neuronal differentiation but not for Growth and Stress Reposne in PC12 cells. J. Cell. Physiol. 207, 12–22 (2006).Arsic, N. et al. Vascular endothelial growth factor stimulates skeletal muscle regeneration in Vivo. Mol. Ther. 10, 844–854 (2004).Borselli, C. et al. Functional muscle regeneration with combined delivery of angiogenesis and myogenesis factors. Proc. Natl. Acad. Sci. USA 107, 3287–3292 (2010).Hanft, J. R. et al. Phase I trial on the safety of topical rhVEGF on chronic neuropathic diabetic foot ulcers. J. Wound Care 17(30–2), 34–7 (2008).Simón-Yarza, T. et al. Vascular endothelial growth factor-delivery systems for cardiac repair: An overview. Theranostics 2, 541–552 (2012).Briquez, P. S., Hubbell, J. A. & Martino, M. M. Extracellular Matrix-Inspired Growth Factor Delivery Systems for Skin Wound Healing. Adv. Wound Care 4, 479–489 (2015).Barthel, A., Ostrakhovitch, E. A., Walter, P. L., Kampkötter, A. & Klotz, L. O. Stimulation of phosphoinositide 3-kinase/Akt signaling by copper and zinc ions: Mechanisms and consequences. Arch. Biochem. Biophys. 463, 175–182 (2007).Ostrakhovitch, E. A., Lordnejad, M. R., Schliess, F., Sies, H. & Klotz, L.-O. Copper ions strongly activate the phosphoinositide-3-kinase/Akt pathway independent of the generation of reactive oxygen species. Arch. Biochem. Biophys. 397, 232–239 (2002).Kaur, K., Gupta, R., Saraf, S. A. & Saraf, S. K. Zinc: The metal of life. Compr. Rev. Food Sci. Food Saf. 13, 358–376 (2014).Coleman, J. E. Zinc proteins: enzymes, storage proteins, transcription factors, and replication proteins. Annu. Rev. Biochem. 61, 897–946 (1992).Fukada, T. & Kambe, T. Molecular and genetic features of zinc transporters in physiology and pathogenesis. Metallomics 3, 662–674 (2011).Murakami, M. & Hirano, T. Intracellular zinc homeostasis and zinc signaling. Cancer Sci. 99, 1515–1522 (2008).Hogstrand, C., Kille, P., Nicholson, R. I. & Taylor, K. M. Zinc transporters and cancer: a potential role for ZIP7 as a hub for tyrosine kinase activation. Trends Mol. Med. 15, 101–111 (2009).Kolenko, V., Teper, E., Kutikov, A. & Uzzo, R. Zinc and zinc transporters in prostate carcinogenesis. Nat. Rev. Urol. 10, 219–26 (2013).Myers, S. A., Nield, A., Chew, G. S. & Myers, M. A. The zinc transporter, Slc39a7 (Zip7) is implicated in glycaemic control in skeletal muscle cells. Plos One 8 (2013).Kambe, T., Tsuji, T., Hashimoto, A. & Itsumura, N. The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism. Physiol. Rev. 95, 749–784 (2015).Jinno, N., Nagata, M. & Takahashi, T. Marginal zinc deficiency negatively affects recovery from muscle injury in mice. Biol. Trace Elem. Res. 158, 65–72 (2014).Taylor, K. M., Hiscox, S., Nicholson, R. I., Hogstrand, C. & Kille, P. Protein Kinase CK2 Triggers Cytosolic Zinc Signaling Pathways by Phosphorylation of Zinc Channel ZIP7. Sci. Signal. 5, ra11–ra11 (2012).Yamasaki, S. et al. Zinc is a novel intracellular second messenger. J. Cell Biol. 177, 637–45 (2007).Sumitani, S., Goya, K., Testa, J. R., Kouhara, H. & Kasayama, S. Akt1 and Akt2 differently regulate muscle creatine kinase and myogenin gene transcription in insulin-induced differentiation of C2C12 myoblasts. Endocrinology 143, 820–828 (2002).Ohashi, K. et al. Zinc promotes proliferation and activation of myogenic cells via the PI3K/Akt and ERK signaling cascade. Exp. Cell Res. 333, 228–237 (2015).Chesters, J. K. In Zinc in human biology 53, 109–118 (1989).Burattini, S. et al. C2C12 murine myoblasts as a model of skeletal muscle development: Morpho-functional characterization. Eur. J. Histochem. 48, 223–233 (2004).Mnatsakanyan, H. et al. Controlled Assembly of Fibronectin Nanofibrils Triggered by Random Copolymer Chemistry. ACS Appl. Mater. Interfaces 7, 18125–18135 (2015).Jeong, J. & Eide, D. J. The SLC39 family of zinc transporters. Molecular Aspects of Medicine 34, 612–619 (2013).Huang, L., Kirschke, C. P., Zhang, Y. & Yan, Y. Y. The ZIP7 gene (Slc39a7) encodes a zinc transporter involved in zinc homeostasis of the Golgi apparatus. J. Biol. Chem. 280, 15456–15463 (2005).Vallee, B. L. & Falchuk, K. H. The biochemical basis of zinc physiology. Physiological reviews 73 (1993).Ganju, N. & Eastman, A. Zinc inhibits Bax and Bak activation and cytochrome c release induced by chemical inducers of apoptosis but not by death-receptor-initiated pathways. Cell Death Differ. 10, 652–61 (2003).Chai, F., Truong-Tran, A. Q., Ho, L. H. & Zalewski, P. D. Regulation of caspase activation and apoptosis by cellular zinc fluxes and zinc deprivation: A review. Immunol. Cell Biol. 77, 272–278 (1999).Smith, P. J., Wiltshire, M., Furon, E., Beattie, J. H. & Errington, R. J. Impact of overexpression of metallothionein-1 on cell cycle progression and zinc toxicity. Am. J. Physiol. Cell Physiol. 295, C1399–C1408 (2008).Bozym, R. A. et al. Free zinc ions outside a narrow concentration range are toxic to a variety of cells in vitro. Exp. Biol. Med. (Maywood). 235, 741–50 (2010).Plum, L. M., Rink, L. & Hajo, H. The essential toxin: Impact of zinc on human health. Int. J. Environ. Res. Public Health 7, 1342–1365 (2010).Chen, C.-J. & Liao, S.-L. Zinc toxicity on neonatal cortical neurons: involvement of glutathione chelation. J. Neurochem. 85, 443–453 (2003).Chassot, A. A. et al. Confluence-induced cell cycle exit involves pre-mitotic CDK inhibition by p27Kip1 and cyclin D1 downregulation. Cell Cycle 7, 2038–2046 (2008).Spencer, S. L. et al. XThe proliferation-quiescence decision is controlled by a bifurcation in CDK2 activity at mitotic exit. Cell 155, 369–383 (2013).Walsh, K. & Perlman, H. Cell cycle exit upon myogenic differentiation. Curr. Opin. Genet. Dev. 7, 597–602 (1997).Puri, P. L. & Sartorelli, V. Regulation of muscle regulatory factors by DNA-binding, interacting proteins, and post-transcriptional modifications. Journal of Cellular Physiology 185, 155–173 (2000).Zammit, P. S., Partridge, T. A. & Yablonka-Reuveni, Z. The skeletal muscle satellite cell: the stem cell that came in from the cold. J Histochem Cytochem 54, 1177–1191 (2006).McCord, M. C. & Aizenman, E. The role of intracellular zinc release in aging, oxidative stress, and Alzheimer’s disease. Front. Aging Neurosci. 6, 1–16 (2014).Dirksen, R. T. Sarcoplasmic reticulum–mitochondrial through-space coupling in skeletal muscle. This paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic. Appl. Physiol. Nutr. Metab. 34, 389–395 (2009).Groth, C., Sasamura, T., Khanna, M. R., Whitley, M. & Fortini, M. E. Protein trafficking abnormalities in Drosophila tissues with impaired activity of the ZIP7 zinc transporter Catsup. Development 140, 3018–3027 (2013).Ellis, C. D. et al. Zinc and the Msc2 zinc transporter protein are required for endoplasmic reticulum function. J. Cell Biol. 166, 325–335 (2004).Koch, U., Lehal, R. & Radtke, F. Stem cells living with a Notch. Development 140, 689–704 (2013).Gardner, S., Anguiano, M. & Rotwein, P. Defining Akt actions in muscle differentiation. Am. J. Physiol. Physiol. 303, C1292–C1300 (2012).Knight, J. D. & Kothary, R. The myogenic kinome: protein kinases critical to mammalian skeletal myogenesis. Skelet. Muscle 1, 29 (2011).Roth, S. M. Genetic aspects of skeletal muscle strength and mass with relevance to sarcopenia. Bonekey Rep. 1, 1–7 (2012).Mebratu, Y. & Tesfaigzi, Y. How ERK1/2 Activation Controls Cell Proliferation and Cell Death Is Subcellular Localization the Answer? Cell Cycle 8, 1168–1175 (2009)