Electromechanical delay components during skeletal muscle contraction and relaxation in patients with myotonic dystrophy type 1
Introduction
Myotonic dystrophy type 1 (DM1, OMIM 160900) is the most frequent form of inherited muscular dystrophy in adulthood, with a prevalence of about 1:8000 [1]. The adult-onset form is the most prevalent, with common clinical exacerbation in the second or third decade of life. Clinical manifestations of adult-onset DM1 involve a broad spectrum of systemic complications, such as cardiac conduction abnormalities and cardiomyopathy, cataract, central nervous system dysfunction, gastrointestinal symptoms, and endocrine abnormalities [1], [2], [3], [4]. The main features at the skeletal muscle level are muscle weakness and grip and percussion myotonia [1]. Distal muscles are generally more compromised than the proximal ones [1], [5].
The mechanisms for muscle weakness, which involves difficulties to perform fine tasks with the hands, foot drop, and facial muscles ptosis, are not fully elucidated. Experimental evidence demonstrates that an alteration in the splicing of several proteins involved in Ca2+ homeostasis and in excitation–contraction coupling mechanisms may play a pivotal role [6], [7], [8], [9], [10]. Myotonia is characterized by a state of pathologically enhanced muscle excitability, in which involuntary trains of action potentials cause a delay in muscle relaxation after contraction [11]. This phenomenon has been associated with the alternative splicing of chloride channels at the muscle fibre level, which determines an alteration of membrane excitability [11]. Altogether, these skeletal muscle alterations in DM1 cause impairments in the cascade of the events involved in muscle contraction and relaxation.
Recently, a surface electromyographic (EMG), mechanomyographic (MMG) and force (F) combined approach has been proposed to get more insights on neuromuscular activation [12], [13], [14], [15], [16] and relaxation [15], [17], [18]. While surface EMG has been already widely used to monitor skeletal muscle electrical activity, MMG records and quantifies the low-frequency transverse oscillations propagating from the active muscle fibres to the skin surface during contraction [12], [1], thus representing the mechanical counterpart of EMG. During muscle contraction, three main mechanisms contribute to MMG generation, as shown in Fig. 1: (i) the gross lateral movement of the contracting fibres at the beginning of contraction (MMG complex), generated by the shortening of contractile elements before the slack of the elastic-connective tissue has been fully taken up, and F has been transmitted to the tendon insertion point [15]; (ii) the subsequent vibrations at the resonance frequency of the muscle (MMG ripple), reflecting the dimensional changes of the active fibres propagating towards the muscle surface [19], [20], [21], [22]; and (iii) the gross lateral movement of the muscle at the end of contraction (R-MMG complex), due to the maximum acceleration of muscle surface caused by cross-bridge detachment and series elastic component (SEC) detensioning [23], [24].
During the on-phase of muscle contraction, the time lag between the onset of muscle electrical activation (EMG onset) and the beginning of F generation (F onset) has been traditionally defined as the electromechanical delay [25]. This time lag includes the electrochemical and mechanical events from motor unit action potential propagation at the sarcolemmal level to force transmission at the tendon insertion point. Similarly, a latency between the cessation of muscle electrical activation (end of EMG signal) and the beginning of F decay has been assessed during the relaxation phase [26], and defined as the relaxation electromechanical delay [27]. This latency spans from the cessation of sarcolemmal electrical activation to the cross-bridges and SEC return towards their pre-contraction status.
When also MMG is recorded, the three signals allow the partitioning of the total electromechanical delay (DelayTOT) into (i) a mainly electrochemical component, which includes the events from the propagation of the motor unit action potential at the sarcolemmal level to myosin head rotation and pressure wave transmission to the skin surface [28], [29], and (ii) a mainly mechanical component, which reasonably provides a potential index of the time required for taking up the muscle–tendon unit slack, before F transmission becomes efficient at the tendon insertion point [12], [13], [14], [16]. When the muscle is electrically activated, the simultaneous recording also of the stimulation current (Stim) offers an additional DelayTOT component between Stim and EMG onset, related to the pre-synaptic and synaptic events [16].
At the end of a voluntary contraction, the total electromechanical delay during relaxation (R-DelayTOT) can be partitioned with the addition of MMG in one mainly electrochemical and three consecutive mainly mechanical components. The first component includes the events from the cessation of the electrical activation of the sarcolemma and the beginning of Ca2+ reuptake in the sarcoplasmic reticulum to the transition of cross-bridges from force-generating to non-force-generating status, together with the pressure wave transmission to the skin surface. The second component comprises the beginning of the rapid change in sarcomere length and the increase in the detachment rate of cross-bridges. The third component incorporates the main phase of cross-bridge detachment and SEC relaxation. Lastly, the fourth component includes the time taken by the cross-bridges and SEC to return towards their pre-contraction status [15], [17], [18].
A similar approach, with the use of high frame rate ultrasound, has been recently proposed in patients with Duchenne dystrophy during contraction [30]. A lengthening of the overall delay due to mechanical component expansion was clearly observed.
In clinical settings, myotonia and muscle weakness are usually determined on patients with DM1 qualitatively or semiquantitatively by the Medical Research Council scale [31], by a dynamometer, and/or by physician's handgrip evaluation [32], [33]. Hence, a valid, non-invasive, and reliable tool to assess the degree of muscle dysfunction in DM1 could be of great interest for clinical trials involving new therapies.
Therefore, the aim of the study was twofold: (i) to assess the reliability and sensitivity of the measurement of the electromechanical delay components during both contraction and relaxation in patients with DM1; and (ii) to evaluate and discuss possible differences in delays' component duration between patients with DM1 and healthy controls (HC).
Section snippets
Participants
Patients with adult-onset DM1 were screened and selected for eligibility if: (i) aged between 18 and 70 yrs; (ii) with genetically confirmation of DM1 diagnosis; (iii) in the presence of the myotonic phenomenon; (iv) without any antimyotonia therapy; (v) without cardiac pacemaker; (vi) without epilepsy; (vii) without concomitant neurological impairments or circulatory diseases at the lower limbs level. Thirteen patients with DM1 (age: 37 ± 14 yrs; body mass: 77 ± 13 kg; stature: 1.79 ± 0.08 m;
Results
None of the participants complained of any heavy discomfort or pain during testing procedures. During SA and SB, one-way ANOVA did not disclose significant differences among the three trials within each session for EMG, MMG and F parameters calculated in TA and VL during electrically evoked and voluntary contractions. The results were therefore pooled and used for further analysis.
Discussion
The novel findings of the study were that: (i) intra- and inter-session reliability of delay components measurement in patients with DM1 was always from high to very high, with adequate levels of sensitivity; and (ii) all components of the delays in both the contraction and relaxation phases were longer in patients with DM1 than in HC. These results suggest that DM1 affected the duration of both the electrochemical and the mechanical events underpinning muscle contraction and relaxation.
Conclusions
Our findings show that the EMG, MMG and F combined approach for DelayTOT and R-DelayTOT components provides reliable and sensitive measurements also in DM1 population. The differences between patients with DM1 and HC in DelayTOT and R-DelayTOT components, together with the high reliability levels, suggest that the proposed EMG, MMG and F combined approach may be used as a valid tool to assess the level of neuromuscular dysfunction in this pathology. This means may be used also to assess the
Acknowledgements
The authors wish to thank all the participants involved in the study, for their patience and committed involvement. The study was supported by the grant #15-6-3016000-106 assigned to Prof. Fabio Esposito by the Department of Biomedical Sciences for Health of the University of Milan.
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2017, Journal of Electromyography and KinesiologyCitation Excerpt :As a matter of fact, EMD can be partitioned into an electrochemical (time lag between EMG and MMG signals onset) and a mechanical (time lag between MMG and F signals onset) component of EMD (Ce et al., 2013a; Ce et al., 2017; Esposito et al., 2016, 2017; Sasaki et al., 2011). The first component includes the events mostly linked to excitation-contraction coupling, whereas the second component comprises the mechanical events related to F transmission by the series elastic components (Ce et al., 2013a, 2014, 2017; Esposito et al., 2016, 2017, 2011; Sasaki et al., 2011). An increase in the whole EMD has been reported after massage on the MTJ (Begovic et al., 2016; Behm et al., 2013).
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2017, Journal of Electromyography and KinesiologyCitation Excerpt :A high level of reliability and sensitivity has been reported for all components during both muscle contraction and relaxation under different experimental models, among which peripheral fatigue (Cè et al., 2014a,b; Rampichini et al., 2014), muscle temperature manipulation (Ce et al., 2013), muscle elongation (Esposito et al., 2011a), contraction intensity (Ce et al., 2013), and joint angles variation (Sasaki et al., 2011). This means can provide reliable data also in patients with myotonic dystrophy (Esposito et al., 2016). A reduction in muscle-tendon unit (MTU) stiffness has been often claimed to explain the lengthening of the different components of delay, in particular those with a predominant mechanical nature (Costa et al., 2010; Esposito et al., 2011a; Hirata et al., 2016; Taniguchi et al., 2015).
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