Muscle fat replacement and contractility in patients with skeletal muscle sodium channel disorders

Abstract

Skeletal muscle sodium channel disorders give rise to episodic symptoms such as myotonia and/or periodic paralysis. Chronic symptoms with permanent weakness are not considered characteristic of the phenotypes. Muscle fat replacement represents irreversible damage that inevitably will impact on muscle strength. This study investigates muscle fat replacement and contractility in patients with pathogenic SCN4A variants compared to healthy controls. T1-weighted and 2-point Dixon MRI of the legs were conducted to assess fat replacement. Stationary dynamometry was used to assess muscle strength. Contractility was determined by maximal muscle contraction divided by cross-sectional muscle area. The average cross-sectional intramuscular fat fraction was greater in patients compared with controls by 2.5% in the calves (95% CI 0.74-4.29%, p = 0.007) and by 2.0% in the thighs (95% CI 0.75-3.2%, p = 0.003). Muscle contractility was less in patients vs. controls by 14-27% (p < 0.05). Despite greater fat fraction and less contractility, absolute strength was not significantly less. This study quantitatively documents greater fat fraction and additionally describes difference in muscle contractility in a large cohort of patients with skeletal muscle sodium channel disorders. The clinical impact of these abnormal findings is likely limited as muscle hypertrophy in the patients served to preserve absolute muscle strength. Subgroup analysis indicated significant difference in phenotype by genotype, however these findings lack statistical significance and serve as inspiration for future researchers to probe into the geno- phenotype relationship in these disorders.Trial registration: The study was registered at http://clinicaltrials.gov (identifier: NCT04808388).

Figure 1

Overview of MRI. (A) Localizer shows the 6 different levels of segmentation on the leg. (B) Example of muscle mapping of the thigh (50%) and calf (33%). (C) T1-w MRI of a 59-year-old patient heterozygous for p.T1313M at 50% length of the thigh. (D–F) Series of T1-w MRI from the same patient at 23, 33 and 43% of the calf, demonstrating significant proximal–distal difference of involvement. In the more distal part of the muscle (at 33% length of the tibia), the gastrocnemius medialis is almost completely replaced by fat.

Figure 2

Fat fraction (FF) and contractile cross-sectional area (CCSA) on the different segments. (A,B) Average fat fraction of calf and thigh. Y-axis is fat fraction in percentage. The difference in FF between the proximal segments and distal segments is significant (p < 0.05). (C,D) Average CCSA on cross sections. Y-axis CCSA in mm². CCSA was significantly higher for patients in the calf, but only nominally so in the thigh, indicating hypertrophy of lower leg muscles.

Figure 3

Fat fraction of single muscles. Fat fraction of individual muscles in patients with SCN4A mutations and healthy controls. Error bars represent standard deviation. Muscles with significant difference between patients and controls are marked with an asterisk (p < 0.05).

Figure 4

Contractility of the four studied muscle groups. Peak torque (Newton-meter)) divided by contractile cross-sectional area (mm²) reflects contractility. The patients have significantly less contractility in all four studied muscle groups (p < 0.005).

Figure 5

Bar plots of contractility and absolute strength between patients and controls. There was a significant difference in contractility for all muscle groups, while absolute strength was only nominally less. Our hypothesis is that increased contractile cross-sectional area compensate for reduced contractility, thus resulting in normalized absolute strength.

Figure 6

Bar plots of contractility in subgroups consisting of p.T1313M variants and non-T1313M variant group controls. Error bars are standard deviation. Both p.T1313M and the non-T1313M variants had significantly less contractility in all studied muscle groups (asterisk; p < 0.05).