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    • Previous studies have implicated impaired

    2018-10-23

    Previous studies have implicated impaired autophagy in Col6a1−/− muscles, which lead to the inability to degrade degenerated mitochondria, causing permeability transition pore opening and eventually resulting to apoptotic cell death (Grumati et al., 2010; Irwin et al., 2003). In the muscles of our Col6a1GT/GT mice, starvation-induced autophagic flux was likewise delayed; there was no accumulation, however, of polyubiquitinated proteins or p62 in muscles (data not shown), both of which are observed in autophagy-deficient mice (Masiero et al., 2009). Furthermore, the pattern of myofiber atrophy was different between Col6a1GT/GT and muscle-specific Atg7−/− muscles (data not shown). We think that the delay of starvation-induced autophagic flux in Col6a1GT/GT muscles is a secondary phenomenon due to metabolic defects as previously suggested (Khan et al., 2009) and not a primary phenomenon. Our findings in Col6a1GT/GT mice provide the insights on therapeutic strategies for UCMD. The muscle weakness Col6a1GT/GT mouse is primarily due to small size of skeletal muscles as there is a paucity or almost lack of myofiber necrosis or degeneration. Although the number of myofibers is reduced, we do not observe prominent myofiber atrophy, suggesting a lack of activation in the atrophy-related signaling. Therefore, therapeutic targets that promote myofiber increase might be useful. Additionally, the observation of selective reduction of twitch force generation in Col6a1GT/GT mice suggests inability of myofibers to contract in synchrony; this is likely due to fibrosis in the whole muscle that expands to the trk receptor area, disrupting the connection between each myofiber. As such, another therapeutic approach can be aimed at the reduction of MPC-mediated fibrosis through cell transplantation of normal/gene-corrected MPCs or supplementation of collagen VI fibrils into the muscle tissues.
    Funding Sources This study is partially supported by Intramural Research Grant (28-6) for Neurological and Psychiatric Disorders of NCNP, by Comprehensive Research on Disability Health and Welfare from the Ministry of Health, Labor and Welfare (H25-Shinkei Kin-Ippan-004) from Japan Agency for Medical Research and Development, AMED, and by JSPS KAKENHI (JP26293214, JP15H04846). M.C.V.M. is supported by the NHGRI Intramural Research Program of the National Institutes of Health, USA.
    Conflicts of Interest
    Author Contributions
    Acknowledgement
    Introduction Preterm birth affects over 15 million newborns each year and is the leading cause of neonatal mortality and morbidity worldwide, complications from which are the leading cause of neonatal mortality, and contributes to 40% of all deaths under the age of five (Lawn et al., 2012; Nour, 2012). The burden of preterm birth is particularly high in resource-poor settings where major risk factors including infection, inadequate nutrition, and poor socioeconomic circumstances are common (Beck et al., 2010). Knowledge of gestational age at the time of birth is critical for population level surveillance, to guide postnatal care by facilitating identification of infants with immediate high-resource needs and guiding developmental assessments (Dosman et al., 2012; DiPietro and Allen, 1991; Bonhoeffer et al., 2006). Differentiation of infants born by preterm birth versus those who are small for gestational age is important to further distinguish infant medical requirements. Unfortunately, in many low-resource environments limited access to prenatal ultrasound dating services and poor recall of self-reported menstrual histories impair accurate and timely gestational age assessment (Rijken et al., 2009; The Partnership for Maternal, Newborn and Child Health, 2006). We and others have recently developed prediction models based on routinely collected newborn metabolic screening profiles that provide accurate estimates of gestational age (Jelliffe-Pawlowski et al., 2015; Ryckman et al., 2015; Wilson et al., 2016). Many newborn screening analytes used to identify rare metabolic conditions may only be reliably ascertained using tandem mass spectrometry – technology requiring significant financial resources and technical expertise. Hemoglobin (Hb) screening for inherited blood disorders such as sickle cell disease and β-thalassemia includes measurement of fetal (HbF) and adult (HbA) Hb levels. HbF is the primary protein for oxygen transport in the developing fetus. Hemoglobin production naturally shifts with advancing gestation from HbF to HbA such that HbF reserves are typically depleted by six months of age (Bank, 2006; Stamatoyannopoulos, 2005), and while residual amounts of HbF continue to be synthesized in adult erythropoiesis, the majority of adults have <1% HbF (Thein et al., 2009). Contrary to the majority of metabolic analytes used in newborn screening programs which are measured by mass spectrometry, Hb may be measured using less technically demanding approaches including high performance liquid chromatography (HPLC) or gel electrophoresis (Association of public health laboratories, 2015; Clarke and Higgins, 2000).