Growth Factors Do Not Improve Muscle Function in Young or Adult mdx Mice

Hepatocyte growth factor; Leukemia inhibitory factor; Muscular regenerationFactor de crecimiento de los hepatocitos; Factor inhibidor de la leucemia; Regeneración muscularFactor de creixement dels hepatòcits; Factor inhibidor de la leucèmia; Regeneració muscularMuscular dystrophies constitute a broad group of genetic disorders leading to muscle wasting. We have previously demonstrated that treating a muscular atrophy mouse model with growth factors resulted in increased muscle mass. In the present study, we treated the Duchenne mouse model mdx for 12 weeks with myogenic growth factors peri- and post-onset of muscular degeneration to explore the effects in the oxidative muscle soleus and the glycolytic muscle extensor digitorum longus (EDL). We found no overall beneficial effect in the peri-onset group at the conclusion of the study. In the post-onset group, the functional improvement by means of electrophysiological examinations ex vivo was mostly confined to the soleus. EDL benefitted from the treatment on a molecular level but did not improve functionally. Histopathology revealed signs of inflammation at the end of treatment. In conclusion, the growth factor cocktail failed to improve the mdx on a functional level.This work was supported by grants from the Lundbeck Foundation (Grant No. R140-2013-13370 to J.V. and T.O.K.), Novo Nordisk Foundation (Grant No. 8091 to J.V. and T.O.K.), AP Møller Foundations (Grant No. 13-222 to T.O.K.), Instituto de Salud Carlos III y Fondos FEDER (FIS Project PI19/01313 to T.P.), and Augustinus Foundation (Grant No. 13-4153 to T.O.K.). None of the funding sources had any involvement in the study, data evaluation, or authoring of the manuscript

Erythropoietin Over-Expression Protects against Diet-Induced Obesity in Mice through Increased Fat Oxidation in Muscles

Erythropoietin can be over-expressed in skeletal muscles by gene electrotransfer, resulting in 100-fold increase in serum EPO and significant increases in haemoglobin levels. Earlier studies have suggested that EPO improves several metabolic parameters when administered to chronically ill kidney patients. Thus we applied the EPO over-expression model to investigate the metabolic effect of EPO in vivo

Restrained Male and Female Occupants in Frontal Crashes: Are We Different?

The safety community is questioning the effect of gender on the performance and assessment ofoccupant protection systems. This study consists of: 1) an investigation of NASS‐CDS data with belted occupantsinvolved in frontal vehicle crashes and 2) a comparison of dummy responses in two matched frontal tests.Because of recent work on a 50th female dummy neck, focus was placed on neck responses. An assessment ofcervical facet angles was also carried out from computed tomography (CT) scans of 423 adult patients.The NASS‐CDS data showed that the relative risk of being seriously injured was higher in females than inmales for crash severities up to 65 km/h. Females had higher overall risks of serious injury in all body regionsexcept for the head and the abdomen. In 25 to 65 km/h crashes, females were more at risk of spine injuriesthan males. In the matched tests, the normalized results showed overall higher biomechanical responses in thefemale than in the male dummy, in particular in the neck region. Airbag interaction with the head/neck complexwas noted with the female dummy. The CT scan data indicated that the cervical facet angles increased with age,becoming more horizontal. The increase was greater in females than in males. The quantification of anatomicalchanges associated with gender is needed to improve physical and/or numerical tools used to assess occupantresponses and to understand differences in injury patterns

Restrained Male and Female Occupants in Frontal Crashes: Are We Different?

The safety community is questioning the effect of gender on the performance and assessment ofoccupant protection systems. This study consists of: 1) an investigation of NASS‐CDS data with belted occupantsinvolved in frontal vehicle crashes and 2) a comparison of dummy responses in two matched frontal tests.Because of recent work on a 50th female dummy neck, focus was placed on neck responses. An assessment ofcervical facet angles was also carried out from computed tomography (CT) scans of 423 adult patients.The NASS‐CDS data showed that the relative risk of being seriously injured was higher in females than inmales for crash severities up to 65 km/h. Females had higher overall risks of serious injury in all body regionsexcept for the head and the abdomen. In 25 to 65 km/h crashes, females were more at risk of spine injuriesthan males. In the matched tests, the normalized results showed overall higher biomechanical responses in thefemale than in the male dummy, in particular in the neck region. Airbag interaction with the head/neck complexwas noted with the female dummy. The CT scan data indicated that the cervical facet angles increased with age,becoming more horizontal. The increase was greater in females than in males. The quantification of anatomicalchanges associated with gender is needed to improve physical and/or numerical tools used to assess occupantresponses and to understand differences in injury patterns

Electroporation Enhanced Effect of Dystrophin Splice Switching PNA Oligomers in Normal and Dystrophic Muscle

Peptide nucleic acid (PNA) is a synthetic DNA mimic that has shown potential for discovery of novel splice switching antisense drugs. However, in vivo cellular delivery has been a limiting factor for development, and only few successful studies have been reported. As a possible modality for improvement of in vivo cellular availability, we have investigated the effect of electrotransfer upon intramuscular (i.m.) PNA administration in vivo. Antisense PNA targeting exon 23 of the murine dystrophin gene was administered by i.m. injection to the tibialis anterior (TA) muscle of normal NMRI and dystrophic mdx mice with or without electroporation. At low, single PNA doses (1.5, 3, or 10 µg/TA), electroporation augmented the antisense exon skipping induced by an unmodified PNA by twofold to fourfold in healthy mouse muscle with optimized electric parameters, measured after 7 days. The PNA splice switching was detected at the RNA level up to 4 weeks after a single-dose treatment. In dystrophic muscles of the MDX mouse, electroporation increased the number of dystrophin-positive fibers about 2.5-fold at 2 weeks after a single PNA administration compared to injection only. In conclusion, we find that electroporation can enhance PNA antisense effects in muscle tissue

Growth Factors Do Not Improve Muscle Function in Young or Adult mdx Mice

Muscular dystrophies constitute a broad group of genetic disorders leading to muscle wasting. We have previously demonstrated that treating a muscular atrophy mouse model with growth factors resulted in increased muscle mass. In the present study, we treated the Duchenne mouse model mdx for 12 weeks with myogenic growth factors peri- and post-onset of muscular degeneration to explore the effects in the oxidative muscle soleus and the glycolytic muscle extensor digitorum longus (EDL). We found no overall beneficial effect in the peri-onset group at the conclusion of the study. In the post-onset group, the functional improvement by means of electrophysiological examinations ex vivo was mostly confined to the soleus. EDL benefitted from the treatment on a molecular level but did not improve functionally. Histopathology revealed signs of inflammation at the end of treatment. In conclusion, the growth factor cocktail failed to improve the mdx on a functional level