Genetic testing for exercise prescription and injury prevention: AIS-Athlome consortium-FIMS joint statement

Abstract Background There has been considerable growth in basic knowledge and understanding of how genes are influencing response to exercise training and predisposition to injuries and chronic diseases. On the basis of this knowledge, clinical genetic tests may in the future allow the personalisation and optimisation of physical activity, thus providing an avenue for increased efficiency of exercise prescription for health and disease. Results This review provides an overview of the current status of genetic testing for the purposes of exercise prescription and injury prevention. As such there are a variety of potential uses for genetic testing, including identification of risks associated with participation in sport and understanding individual response to particular types of exercise. However, there are many challenges remaining before genetic testing has evidence-based practical applications; including adoption of international standards for genomics research, as well as resistance against the agendas driven by direct-to-consumer genetic testing companies. Here we propose a way forward to develop an evidence-based approach to support genetic testing for exercise prescription and injury prevention. Conclusion Based on current knowledge, there is no current clinical application for genetic testing in the area of exercise prescription and injury prevention, however the necessary steps are outlined for the development of evidence-based clinical applications involving genetic testing

Skeletal muscle repair in a mouse model of nemaline myopathy

Nemaline myopathy (NM), the most common non-dystrophic congenital myopathy, is a variably severe neuromuscular disorder for which no effective treatment is available. Although a number of genes have been identified in which mutations can cause NM, the pathogenetic mechanisms leading to the phenotypes are poorly understood. To address this question, we examined gene expression patterns in an NM mouse model carrying the human Met9Arg mutation of alpha-tropomyosin slow (Tpm3). We assessed five different skeletal muscles from affected mice, which are representative of muscles with differing fiber-type compositions, different physiological specializations and variable degrees of pathology. Although these same muscles in non-affected mice showed marked variation in patterns of gene expression, with diaphragm being the most dissimilar, the presence of the mutant protein in nemaline muscles resulted in a more similar pattern of gene expression among the muscles. This result suggests a common process or mechanism operating in nemaline muscles independent of the variable degrees of pathology. Transcriptional and protein expression data indicate the presence of a repair process and possibly delayed maturation in nemaline muscles. Markers indicative of satellite cell number, activated satellite cells and immature fibers including M-Cadherin, MyoD, desmin, Pax7 and Myf6 were elevated by western-blot analysis or immunohistochemistry. Evidence suggesting elevated focal repair was observed in nemaline muscle in electron micrographs. This analysis reveals that NM is characterized by a novel repair feature operating in multiple different muscles.Despina Sanoudou, Mark A. Corbett, Mei Han, Majid Ghoddusi, Mai-Anh T. Nguyen, Nicole Vlahovich, Edna C. Hardeman, and Alan H. Begg

A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction

MLKL is the essential effector of necroptosis, a form of programmed lytic cell death. We have isolated a mouse strain with a single missense mutation, Mlkl(D139V), that alters the two-helix 'brace' that connects the killer four-helix bundle and regulatory pseudokinase domains. This confers constitutive, RIPK3 independent killing activity to MLKL. Homozygous mutant mice develop lethal postnatal inflammation of the salivary glands and mediastinum. The normal embryonic development of Mlkl(D139V) homozygotes until birth, and the absence of any overt phenotype in heterozygotes provides important in vivo precedent for the capacity of cells to clear activated MLKL. These observations offer an important insight into the potential disease-modulating roles of three common human MLKL polymorphisms that encode amino acid substitutions within or adjacent to the brace region. Compound heterozygosity of these variants is found at up to 12-fold the expected frequency in patients that suffer from a pediatric autoinflammatory disease, chronic recurrent multifocal osteomyelitis (CRMO). Necroptosis is a regulated form of inflammatory cell death driven by activated MLKL. Here, the authors identify a mutation in the brace region that confers constitutive activation, leading to lethal inflammation in homozygous mutant mice and providing insight into human mutations in this region

Magnetic resonance imaging and freehand 3-D ultrasound provide similar estimates of free achilles tendon shape and 3-D geometry

The purpose of this study was to assess the similarity of free Achilles tendon shape and 3-D geometry between magnetic resonance imaging (MRI) and freehand 3-D ultrasound (3-DUS) imaging methods. Fourteen elite/sub-elite middle-distance runners participated in the study. MRI and 3-DUS scans of the Achilles tendon were acquired on two separate imaging sessions, and all 3-D reconstructions were performed using identical methods. Shape similarity of free Achilles tendon reconstructed from MRI and 3-DUS data was assessed using Jaccard index, Hausdorff distance and root mean square error (RMSE). The Jaccard index, Hausdorff distance and RMSE values were 0.76 ± 0.05, 2.70 ± 0.70 and 0.61 ± 0.10 mm, respectively. The level of agreement between MRI and 3-DUS for free Achilles tendon volume, length and average cross-sectional area (CSA) was assessed using Bland-Altman analysis. Compared to MRI, freehand 3-DUS overestimated volume, length and average CSA by 30.6 ± 15.8 mm3 (1.1% ± 0.6%), 0.3 ± 0.7 mm (0.6% ± 1.9%) and 0.3 ± 1.42 mm2 (0.4% ± 2.0%), respectively. The upper and lower limits of agreement between MRI and 3-DUS for volume, length and average CSA were −0.4 to 61.7 mm3 (−0.2% to 2.3%), −1.0 to 1.5 mm (−3.2% to 4.5%) and −2.5 to 3.1 mm2 (−3.5% to 4.3%), respectively. There were no significant differences between imaging methods in CSA along the length of the tendon. In conclusion, MRI and freehand 3-DUS may be considered equivalent methods for estimating shape and 3-D geometry of the free Achilles tendon. These findings, together with the practical benefits of being able to assess 3-D Achilles tendon shape and geometry in a laboratory environment and under isometric loading, make 3-DUS an attractive alternative to MRI for assessing 3-D free Achilles tendon macro-structure in future studies. © 2019 World Federation for Ultrasound in Medicine & Biolog

Cytoskeletal Tropomyosin Tm5NM1 Is Required for Normal Excitation–Contraction Coupling in Skeletal Muscle

The functional diversity of the actin microfilaments relies in part on the actin binding protein tropomyosin (Tm). The muscle-specific Tms regulate actin-myosin interactions and hence contraction. However, there is less known about the roles of the numerous cytoskeletal isoforms. We have shown previously that a cytoskeletal Tm, Tm5NM1, defines a Z-line adjacent cytoskeleton in skeletal muscle. Recently, we identified a second cytoskeletal Tm in this region, Tm4. Here we show that Tm4 and Tm5NM1 define separate actin filaments; the former associated with the terminal sarcoplasmic reticulum (SR) and other tubulovesicular structures. In skeletal muscles of Tm5NM1 knockout (KO) mice, Tm4 localization was unchanged, demonstrating the specificity of the membrane association. Tm5NM1 KO muscles exhibit potentiation of T-system depolarization and decreased force rundown with repeated T-tubule depolarizations consistent with altered T-tubule function. These results indicate that a Tm5NM1-defined actin cytoskeleton is required for the normal excitation–contraction coupling in skeletal muscle