Myotonia congenita in a Greek cohort: Genotype spectrum and impact of the CLCN1:c.501C > G variant as a genetic modifier.

INTRODUCTION/AIMS: Myotonia congenita (MC) is the most common hereditary channelopathy in humans. Characterized by muscle stiffness, MC may be transmitted as either an autosomal dominant (Thomsen) or a recessive (Becker) disorder. MC is caused by variants in the voltage-gated chloride channel 1 (CLCN1) gene, important for the normal repolarization of the muscle action potential. More than 250 disease-causing variants in the CLCN1 gene have been reported. This study provides an MC genotype-phenotype spectrum in a large cohort of Greek patients and focuses on novel variants and disease epidemiology, including additional insights for the variant CLCN1:c.501C > G. METHODS: Sanger sequencing for the entire coding region of the CLCN1 gene was performed. Targeted segregation analysis of likely candidate variants in additional family members was performed. Variant classification was based on American College of Medical Genetics (ACMG) guidelines. RESULTS: Sixty-one patients from 47 unrelated families were identified, consisting of 51 probands with Becker MC (84%) and 10 with Thomsen MC (16%). Among the different variants detected, 11 were novel and 16 were previously reported. The three most prevalent variants were c.501C > G, c.2680C > T, and c.1649C > G. Additionally, c.501C > G was detected in seven Becker cases in-cis with the c.1649C > G. DISCUSSION: The large number of patients in whom a diagnosis was established allowed the characterization of genotype-phenotype correlations with respect to both previously reported and novel findings. For the c.501C > G (p.Phe167Leu) variant a likely nonpathogenic property is suggested, as it only seems to act as an aggravating modifying factor in cases in which a pathogenic variant triggers phenotypic expression.

Muscle Ultrasound Echo Intensity and Fiber Type Composition in Young Females.

Ultrasonography has been extensively used to evaluate skeletal muscle morphology. The echo intensity, i.e., the mean pixel intensity of a specific region of interest in an ultrasound image, may vary among muscles and individuals with several intramuscular parameters presumed to influence it. The purpose of this study was to investigate the correlation between muscle echo intensity and muscle fiber type composition in humans. Thirteen female physical education students (age: 22.3 ± 5.4 years, height: 1.63 ± 0.06 m, body mass: 59.9 ± 7.4 kg) with no history of systematic athletic training participated in the study. Body composition with dual X-ray absorptiometry, leg-press maximum strength (1-RM), echo intensity, and the cross-sectional area (CSA) of the vastus lateralis (VL) muscle according to ultrasonography were measured. Muscle biopsies were harvested from the VL site where the echo intensity was measured. VL echo intensity was not significantly correlated with the percentage of type I muscle fibers or with the percentage area of type I muscle fibers. However, when VL echo intensity was corrected for the subcutaneous fat thickness at the site of the measurement, it was significantly correlated with the percentage of type I muscle fibers (r = 0.801, p < 0.01) and the percentage area of type I muscle fibers (r = 0.852, p < 0.01). These results suggest that the echo intensity of the vastus lateralis muscle corrected for the subcutaneous fat thickness at the measurement site may provide an estimate of the muscle fiber type composition, at least in young moderately trained females.

Recovery during Successive 120-min Football Games: Results from the 120-min Placebo/Carbohydrate Randomized Controlled Trial.

PURPOSE: This study aimed to examine the recovery kinetics (i.e., time-dependent changes) of performance-related variables between two 120-min male football games performed 3 d apart with and without carbohydrate supplementation. METHODS: Twenty male players (20 ± 1 yr; body fat, 14.9% ± 5.1%; maximal oxygen consumption, 59.4 ± 3.7 mL·kg -1 ·min -1 ) participated in two 120-min football games (G1, G2) according to a randomized, two-trial, repeated-measures, crossover, double-blind design. Participants received carbohydrate/placebo supplements during recovery between games. Field activity was monitored during the games. Performance testing and blood sampling were performed before and at 90 and 120 min of each game. Muscle biopsies were collected at baseline and at 90 and 120 min of G1 and pre-G2. RESULTS: Compared with G1, G2 was associated with reduced total distance (10,870 vs 10,685 m during 90 min and 3327 vs 3089 m during extra 30 min; P = 0.007-0.038), average (6.7 vs 6.2 km/h during extra 30-min game-play; P = 0.007) and maximal speed (32.2 vs 30.2 km/h during 90 min and 29.0 vs 27.9 km/h during extra 30 min; P < 0.05), accelerations/decelerations ( P < 0.05), and mean heart rate ( P < 0.05). Repeated sprint ability ( P < 0.001), jumping ( P < 0.05), and strength ( P < 0.001) performance were compromised before and during G2. Muscle glycogen was not restored at G2 baseline ( P = 0.005). Extended game-play reduced lymphocyte, erythrocyte counts, hematocrit, hemoglobin, reduced glutathione ( P < 0.05) and increased delayed onset of muscle soreness, creatine kinase activity, blood glycerol, ammonia, and protein carbonyls ( P < 0.05) before and during G2. Pax7 + ( P = 0.004) and MyoD + cells ( P = 0.019) increased at baseline G2. Carbohydrate supplementation restored performance and glycogen, reduced glycerol and delayed onset of muscle soreness responses, and increased leukocyte counts and Pax7 + and MyoD + cells. CONCLUSIONS: Results suggest that extended football games induce a prolonged recovery of performance, which may be facilitated by carbohydrate supplementation during a congested game fixture.

Retrospective analysis of persistent HyperCKemia with or without muscle weakness in a case series from Greece highlights vast DMD variant heterogeneity.

BACKGROUND: Persistent hyperCKemia results from muscle dysfunction often attributed to genetic alterations of muscle-related genes, such as the dystrophin gene (DMD). Retrospective assessment of findings from DMD analysis, in association with persistent HyperCKemia, was conducted. PATIENTS AND METHODS: Evaluation of medical records from 1354 unrelated cases referred during the period 1996-2021. Assessment of data concerning the detection of DMD gene rearrangements and nucleotide variants. RESULTS: A total of 730 individuals (657 cases, 569 of Greek and 88 of Albanian origins) were identified, allowing an overall estimation of dystrophinopathy incidence at ~1:3800 live male births. The heterogeneous spectrum of 275 distinct DMD alterations comprised exon(s) deletions/duplications, nucleotide variants, and rare events, such as chromosome translocation {t(X;20)}, contiguous gene deletions, and a fused gene involving the DMD and the DOCK8 genes. Ethnic-specific findings include a common founder variant in exon 36 ('Hellenic' variant). CONCLUSIONS: Some 50% of hyperCKemia cases were characterized as dystrophinopathies, highlighting that DMD variants may be considered the most common cause of hyperCKemia in Greece. Delineation of the broad genetic and clinical heterogeneity is fundamental for actionable public health decisions and theragnosis, as well as the establishment of guidelines addressing ethical considerations, especially related to the mild asymptomatic patient subgroup.

Weak Association Between Vastus Lateralis Muscle Fiber Composition and Fascicle Length in Young Untrained Females.

The aim of the study was to investigate the relationships between vastus lateralis muscle fiber length and fiber type composition in individuals with minimal exposure to systematic resistance/power training. In sixty female physical education students (age: 21.03 ± 2.1 years, body weight: 59.8 ± 9.7 kg, body height: 166.2 ± 6.5 cm), with no experience in systematic training, lean body mass, VL muscle architecture and fiber composition type, countermovement jumping (CMJ) performance, and isometric leg press rate of force development were evaluated. Data were analyzed for all participants, as well as two equally numbered groups assigned according to their maximum countermovement jumping power (High-Power or Low-Power group). Significant but low correlations were found between type II muscle fiber percentage and fascicle length (N = 60, p < 0.05). Significant correlations were found between type IIa and IIx muscle fiber percentage cross-sectional area (%CSA) and fascicle length (N = 60; r = 0.321, and r = 0.378; respectively, p < 0.05). These correlations were higher for the High-Power group (r = 0.499, and r = 0.522; respectively, p < 0.05), and lower, and nonsignificant, for the Low-Power group. The best predictor of strength/power performance was the lean body mass of the lower extremities (r = 0.389-0.645, p < 0.05). These results suggest that in females with minimal exposure to systematic training, fascicle length may be weakly linked with type II fiber areas, only in females with high-power profiles.

Effect of exercise training on functional capacity and body composition in myotonic dystrophy type 2 patients.

BACKGROUND: Myotonic dystrophy type 2 (DM2) is a neuromuscular disorder characterized by myotonia and muscle weakness, with no medical treatment to prevent a decline in decline. It is unknown whether exercise training is effective in DM2. The aim of this study was to investigate the effect of exercise training on functional capacity and body composition in these patients. METHODS: Body composition and functional capacity were evaluated at the beginning (T1) and end (T2) of a 12 wk control period, and again after 16 wk of exercise training (T3) in 10 patients. RESULTS: No changes were recorded after the control period. Handgrip strength, 5× sit to stand, timed up and go, 6 min walk distance, lean body mass (LBM), and bone mineral density (BMD) increased while arterial pressure decreased after training. CONCLUSIONS: These results suggest that supervised exercise training improves functional capacity, LBM, and BMD in ambulatory DM2 patients.

Changes in Muscle Power and Muscle Morphology with Different Volumes of Fast Eccentric Half-Squats.

The aim of the study was to evaluate power performance and muscle morphology adaptations in response to 5 weeks of fast-eccentric squat training (FEST) performed twice per week, with three different training volumes. Twenty-five moderately trained females were assigned into three groups performing eight repetitions of FEST of either four sets (4 × 8 group; N = 9), 6 sets (6 × 8 group; N = 8) or eight sets (8 × 8 group, N = 8). Before and after the intervention, countermovement jumping height (CMJh) and power (CMJp), half squat maximal strength (1-RM), quadriceps cross-sectional area (QCSA) and vastus lateralis (VL) architecture and fiber type composition were evaluated. Significant increases (p < 0.05) were found for all groups, with no differences among them in 1-RM (4 × 8: 14.8 ± 8.2%, 6 × 8: 13.1 ± 9.2% and 8 × 8: 21.6 ± 7.0%), CMJh (4 × 8: 12.5 ± 8.5%, 6 × 8: 11.3 ± 9.3% and 8 × 8: 7.0 ± 6.2%), CMJp (4 × 8: 9.1 ± 6.0%, 6 × 8: 7.1 ± 5.2% and 8 × 8: 5.0 ± 3.9%) and QCSA (4 × 8: 7.7 ± 4.7%, 6 × 8: 9.0 ± 6.8% and 8 × 8: 8.2 ± 6.5%). Muscle fiber type distribution remained unaltered after training in all groups. VL fascicle length increased and fascicle angle decreased only in 6 × 8 and 8 × 8 groups. In conclusion, four sets of eight fast-eccentric squats/week increase lower body power and strength performance and maintain type IIX muscle fibers after 5 weeks, at least in moderately trained females.

Fiber Type Composition and Rate of Force Development in Endurance- and Resistance-Trained Individuals.

Methenitis, S, Spengos, K, Zaras, N, Stasinaki, A-N, Papadimas, G, Karampatsos, G, Arnaoutis, G, and Terzis, G. Fiber type composition and rate of force development in endurance- and resistance-trained individuals. J Strength Cond Res 33(9): 2388-2397, 2019-The purpose of the study was to investigate the relationship between muscle fiber composition and the rate of force development (RFD) in well-trained individuals with different training background. Thirty-eight young men with different training background participated: 9 endurance runners, 10 power-trained individuals, 9 strength-trained individuals, and 10 sedentary individuals. They performed maximal isometric leg press for the measurement of RFD. Body composition (dual x-ray absorptiometry) and vastus lateralis fiber type composition were also evaluated. When all participants were examined as a group, moderate correlations were found between the percent of type II muscle fibers and RFD between 100 and 600 milliseconds (r = 0.321-0.497; p ≤ 0.05). The correlation coefficients were higher for the cross-sectional area (CSA) and the %CSA of type II and IIx muscle fibers (r = 0.599-0.847; p < 0.001). For the power group, RFD up to 250 milliseconds highly correlated with % type IIx muscle fibers and type IIx fiber CSA (r = 0.670-0.826; p ≤ 0.05), as well as with %CSA of type IIx fibers (r = 0.714-0.975; p ≤ 0.05). Significant correlations were found between the relative RFD (·kg lower extremities lean mass) and CSA-%CSA of type II and IIx fibers for the power group (r = 0.676-0.903; p ≤ 0.05). No significant correlations were found between muscle morphology and RFD for the other groups. In conclusion, the present data suggest that there is a strong link between the type IIx muscle fibers and early RFD and relative RFD in power-trained participants. Type II fibers seem to be moderately linked with RFD in non-power-trained individuals.

Effects of exercise training during infusion on late-onset Pompe disease patients receiving enzyme replacement therapy.

Pompe disease is an autosomal recessive disorder caused by the deficiency of acid α-glucosidase resulting in lysosomal accumulation of glycogen and abnormal autophagic function. The late-onset form of the disease is characterized by progressive skeletal and respiratory muscle dysfunction. Enzyme replacement therapy (ERT, Genzyme Corporation, Cambridge, MA, USA) was recently introduced and resulted in significant prolongation of the life expectancy of the patients with the infantile form while the results were less significant for the late-onset form. It has been postulated that the weak influence of ERT in late-onset patients might be due to a non-effective delivery of the recombinant enzyme to the skeletal muscles perhaps due to the relatively low blood flow to the resting skeletal muscles during infusion. Exercise training acutely increases the blood flow to the exercising muscles. Thus, it was hypothesized that exercise training during enzyme infusion might increase the effectiveness of the ERT therapy. Five late-onset Pompe disease patients receiving ERT and following regular exercise training for approximately 10 months, followed a 6-month period of exercise training during infusion of the recombinant enzyme. Before and after this period, body composition, isometric strength and 6 minute walking distance were determined. Analysis of the results revealed that none of these parameters changed significantly after the 6-month intervention period (e.g. 6 minute walking distance before: 532±31 m, vs. after: 527±29 m, P=0.246). These results suggest that exercise training during infusion may not add significant functional changes in late-onset Pompe patients receiving ERT and undergoing regular exercise training.