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NEUROMUSCULAR FUNCTION AND FATIGABILITY
Fatigue and fatigability
Fatigue is a multifactorial and complex phenomenon that generally occurs following a stressor-induced change in the homeostasis of the organism. However, despite the large and evolving literature in the field of exercise physiology, a clear and complete definition of fatigue is still hard to find. In materials engineering, fatigue describes a structural failure that occurs following repeated cyclic loads, even when the experienced stress range is far below the static material strength (Britannica Online Encyclopedia 2021). This concept could be extended to exercise physiology, attributing 3 main characteristics to fatigue (Craig and Ratel 2009): i) an alteration in the homeostasis of one or more biological systems, ii) this alteration is reversible with recovery and iii) it can happen before (latent fatigue) an observable decrease in the performance (i.e. exhaustion). Since the pioneer works of the Italian physiologist Angelo Mosso (1846-1910), it has been acknowledged that exercise-induced fatigue is a complex phenomenon that encompass impairments from the central nervous system [CNS,(Enoka et al. 2011)], down to the skeletal muscle level. This results in both the sensation of tiredness and the decline in muscle force and performance (Enoka et al. 2011; Taylor et al. 2016a; Enoka and Duchateau 2016). To separate those two distinct phenomenon, in recent years some authors suggested that the term “fatigue” should be separated in “perceived fatigability” and “performance fatigability” (Enoka and Duchateau 2016). “Perceived fatigability” is usually adopted to indicate the sensation of discomfort and lack of energy caused by exercise or clinical conditions (Twomey et al. 2017) and generally measured through visual scales of perceived effort/fatigue that answer to general questions like “how do you feel?” (Micklewright et al. 2017; St Clair Gibson et al. 2018). “Performance fatigability” indicates a decrease in observable performance (e.g. force, power) following exercise (Enoka and Duchateau 2016) and is usually quantified using dynamometers.
Performance fatigability and its etiology are typically quantified by evaluating impairments in the neuromuscular system (Figure 1), which is composed by the motor cortex (supraspinal or cortical component), the spinal motoneuronal pool (spinal component), and the motor units down to the actin-myosin bridges (peripheral or muscular component; Figure 1). A current definition of performance fatigability could be “a response that is less than the expected or anticipated contractile response, for a given stimulation” (Macintosh and Rassier 2002). Usually, during exercise, afferent feedbacks stressed by exertion converge to the CNS, which could modulate the motor drive output to the muscles. This can be achieved by influencing the excitability/inhibition of three sites: the motor cortex, the motoneuron pool in the spinal cord pathway and/or the single motor units (Gandevia 2001; Ranieri and Di Lazzaro 2012; Heckman and Enoka 2012). Thus, performance fatigability could be caused by a lack in energetic substrates, oxygen supply, metabolite accumulation or structural alteration that happen within the muscle (impairments in contractile function), but also by alterations in the voluntary activation capacity of the skeletal muscle by the CNS (Figure 1).
Figure 1. Schematic representation of the neuromuscular system and the sites / mechanisms that could be impaired during physical efforts. From: (Hunter 2018).
Central origin of performance fatigability
The central origin of performance fatigability is multifactorial and depends on the population considered, the environmental conditions and the kind of task performed. From a practical point of view, it indicates the inability of the CNS to recruit the α-motoneurons at a frequency sufficient to provoke a tetanus during maximal contractions (Millet et al. 2011). Central alterations are usually defined as a decrease in voluntary activation of the muscle during exercise by processes not attributable to mental fatigue (Gandevia 2001).
Different biological processes have been hypothesized to cause fatigue-related alterations within the CNS. The first phenomenon has been observed during prolonged exercise and involves the synthesis and metabolism of some neurotransmitters of the CNS such as serotonin, dopamine and noradrenalin that influence the activity of the serotonergic system (Meeusen et al. 2006). Activity of the serotonergic system increases during fatiguing endurance exercise, causing sleepiness and general sensation of tiredness, and reduces the excitability (and thus the recruitment) of the motor unit pool (Newsholme et al. 1987; Newsholme and Blomstrand 1996). An increase in the serotonergic system activity has also been shown to impair motor coordination, proprioception and the ability to focus, and to increase the reaction time to an external stimulus (Gandevia 2001). Moreover, a decrease in the dopamine/serotonin ratio is well correlated with the decrease in maximal muscular voluntary activation (Meeusen et al. 2007).
Other biochemical processes have been proposed to contribute to the development of voluntary activation impairments, such as the influence of several neurotransmitters [GABA, ACTH, glutamate and adenosine; (Meeusen et al. 2006)] that could be released in the CNS during exercise. These neurotransmitters can i) influence the neuronal excitation/inhibition within the motor cortex (GABA, glutamate), ii) reduce the secretion of dopamine and noradrenaline (adenosine) or iii) influence the energetic balance of the organism (ACTH). Other possible contributors to the alteration of the nervous system include i) the production of interleukins during exercise that provide an hormonal-like feedback (Nybo and Secher 2004; Zając et al. 2015), ii) an increased concentration of ammonium ions in the brain blood flow and iii) a reduction in the energetic precursors and oxygen to sustain the brain and muscle activity (Nybo and Secher 2004; Meeusen et al. 2006).
Neural feedback from the muscles
The capacity to generate and transmit the voluntary drive to the muscles could be directly influenced by a feedback neural circuitry, i.e. inhibitory neurons that are activated by high concentrations of metabolic byproducts generated during exercise. This function has been mainly attributed to the groups III and IV afferent inputs (Gandevia 2001; Zając et al. 2015; Amann et al. 2015), which consist in myelinated and unmyelinated neural afferents to the CNS whose role is primarily to adjust the hearth rate, respiratory frequency and others hemodynamics factors during exercise (Amann et al. 2015). In this view, fatigability at CNS level would be considered as secondary to peripheral alterations (Amann et al. 2011). Afferent inhibitory burst within the spinal circuitry has been recognized as the main responsible for the reduction in spinal transmission. Thus, the motor drive to the α-motoneurons and then to the muscle can be reduced importantly at spinal level. Finally, intrinsic changes within the motoneurons and interneurons due to repetitive activation could also be responsible for spinal fatigability (Kernell and Monster 1982; Kukulka et al. 1986). For instance, repetitive neuromodulator activation induces a dendritic persistent inward current that may increase the gain of motor excitability from 6 to 10 fold (Heckman et al. 2008). This phenomenon is mediated by the CNS, i.e. noradrenergic neurons (from the locus coeruleus) and serotoninergic neurons (from the caudal raphe nucleus) send their axons down to the spinal motoneurons. Serotonin release may increase α-motoneuron excitability when acting on some specific receptors while high concentrations of serotonin leads to reduction in responsiveness of the targeted α-motoneuron (Cotel et al. 2013; Taylor et al. 2016b). As serotonin release in those areas might decrease with exercise, this would result in a progressive decrease in spinal loop excitability during long lasting fatiguing tasks (Kavanagh et al. 2019).
Peripheral origin of performance fatigability
The term “peripheral” denotes all the alterations that occur below the neuromuscular junction and that are associated with a loss in functionality of the contractile apparatus (e.g. diminution of sarcolemmal excitability, impairments in the actin-myosin coupling, metabolites accumulation and acute structural damage). The mechanisms that could be impaired are dependent on the type, intensity and duration of the task. The cascade of mechanisms that goes from the electrical signal to the neuromuscular junction to the force generation are presented in Figure 2. Two main categories of phenomena are accounted for this loss in contractile function: ionic and metabolic impairments.
Ionic phenomena linked to the synaptic and membrane transmission of the action potential have a large safety factor. This means that the concentration of ions displaced from the activity of the Na+ /K+ pump and the displacement of Cl- ions, largely overcome the quantity needed for an overshoot (action potential). Then, depletion is unlikely and this mechanism probably does not limit exercise performance (Allen et al. 2008b, a). However, exceptions occur in case of transient ions accumulations in small volumes (Sejersted and Sjøgaard 2000). This is the case for the action potential transmission across the T-tubules, because of their very small volume [less than 1% of the muscle; (Farrell et al. 2011)]. During the repeated activity of the Na+/K+pump, there is an extracellular accumulation of K+ ions and depletion of Na+ ions. Those transitory events increase in magnitude with high discharge frequencies, inactivating the Na+ channels and reducing the action potential transmission. Consequently, there is a lower activation of the voltage-dependent ryanodine receptors, and in turn a reduced release of Ca2+ from the sarcoplasmic reticulum (SR) (MacLaren and Morton 2012).
Nevertheless, these localized ionic phenomena in vivo have been considered secondary (Allen et al. 2008b). Indeed, other ionic mechanism have been hypothesized to compensate for the K+ accumulation, such as a reduction in the conductance of the ions Cl- caused by the drop in pH during exercise (Pedersen et al. 2005). Furthermore, other alterations in contractile function occur before the accumulation of ions in the T-tubules, and could play an important role in Ca2+ release (Allen et al. 2008a; MacLaren and Morton 2012). One of those involves the local depletion of ATP in the interspace between T-tubules and SR(Stewart et al. 2007). In this interspace, the high concentration of glycolytic enzymes can be unable to produce ATP in case of lack in substrate supply (Ørtenblad et al. 2011). This ATP is necessary for the functioning of the ATP-dependent channels like the Na+/K+ pumps or the Sarco-Endoplasmic Reticulum Calcium ATPase (SERCA), which are responsible for the calcium reuptake (Ørtenblad et al. 2011). Reduction in calcium reuptake has been associated with the slowdown in the rate of muscle relaxation observed with fatigue (Vernillo et al. 2020).
Other ionic mechanisms of fatigability consists in ionic imbalance. Magnesium (Mg2+) depletion favours an excessive quantity of Ca2+ to binds the troponin C, resulting in hypercontractility and muscular cramps/spasm (de Baaij et al. 2015). In case of ATP depletion, there is a rise in free Mg2+ (Westerblad and Allen 1992). Accumulation of Mg2+ could also have deleterious effects on SERCA and ryanodine receptors, and thus on Ca2+ release and reuptake (Blazev and Lamb 1999; Dias et al. 2006; de Baaij et al. 2015).
Metabolic mechanisms: the role of pH and free phosphates
Classically, a decrease in oxygen uptake from the blood flow has been linked to the utilisation of the lactic anaerobic system and accounted as responsible for the production of lactate (La-) and H+ ions. H+ ions accumulation decreases cellular pH, inducing alterations in contractile function. In particular, the drop in pH seems associated with the slowing of the rate of force relaxation(Westerblad and Allen 2002). However, several studies showed that the drop in pH and the presence of lactate would not be determinant for other contractile function impairments (Stackhouse et al. 2001a; Westerblad and Allen 2002; Allen et al. 2008b; MacLaren and Morton 2012).
In the last few decades, research focusing on the metabolic causes of peripheral origin of neuromuscular fatigue found a key role played by the free phosphate (Pi) released following exercise, as it regulates several biochemical pathways (Baker et al. 2010). Accumulation of Pi has been shown to reduce or even directly inhibit the formation of actin-myosin bridges and bind the calcium released from the SR, blocking its affinity with the troponin C and SERCA (Dahlstedt et al. 2001; Westerblad and Allen 2002; Allen et al. 2008b; Debold 2012). Concomitant with the increase in Pi production, high energetic turnover causes the depletion of glucose and glycogen. Impairments in glucose or energetic supply to the muscle leads to ATP depletion and the accumulation of ADP and AMP (Cooke et al. 1988; Allen et al. 2008b). ADP and AMP are important allosteric effectors involved in cell and glucose metabolisms, regulating the energetic production and consumption (Jensen et al. 2009).
Concentration of free radicals
Prolonged energetic turnover during exercise causes the rise in concentration of by-products such as free radical species, i.e. the reactive oxygen species (ROS) and reactive nitrogen species (RNS) (Reid 2008; Ferreira and Reid 2008), which could damage the cell structure. The production of free radicals could increase dramatically during intense and prolonged exercises as well as in ischemic conditions, dehydration, UV radiation exposure, heat, infections, lack of sleep or poor diets (Lewis et al. 2015). ROS/RNS accumulation causes muscle structural damage at the muscular proteins level, in particular to troponin C, myosin and actin, reducing in turn Ca2+ sensibility and contractile force (Scherer and Deamer 1986; Snook et al. 2008; Debold 2012). An association between those free radical species and performance fatigability has been directly observed by experimentally exposing muscle fibers to ROS-scavengers, which reduced the concentration of free radicals within the cell. As a result, force depression was attenuated (Moopanar and Allen 2005, 2006).
Table of contents :
1. NEUROMUSCULAR FUNCTION AND FATIGABILITY
1.1 Fatigue and fatigability
1.2 Central origin of performance fatigability
1.2.1 Biological processes
1.2.2 Neural feedback from the muscles
1.3 Peripheral origin of performance fatigability
1.3.1 Ionic mechanism
1.3.2 Metabolic mechanisms: the role of pH and free phosphates
1.3.3 Concentration of free radicals
2. NON-INVASIVE MEASUREMENT OF PERFORMANCE FATIGABILITY
2.1 Neuromuscular performance
2.2 Performance fatigability
2.3 Performance fatigability etiology
2.3.1 Measurement of peripheral alterations
2.3.2 Measurement of cortical and spinal excitability and inhibition
2.3.3 Voluntary activation
3. NEUROMUSCULAR CHANGES WITH AGING
3.1 Neuromuscular alterations with age
3.1.1 Properties of the motor units
3.1.2 Age-related changes in the motor units
3.1.3 Changes in single muscle fibers function with age
3.1.4 Age-related alterations in motor drive and voluntary activation
3.2 Muscle function: force and power
3.2.1 Contraction mode affects the age-related differences
3.2.2 Sex-related differences in muscle function with age
4. AGE-RELATED ALTERATIONS IN PERFORMANCE FATIGABILITY
4.1 Isometric tasks
4.2 Concentric tasks
5. EFFECTS OF PHYSICAL ACTIVITY ON NEUROMUSCULAR FUNCTION OBJECTIVES AND HYPOTHESES MATERIALS AND METHODS
1. EXPERIMENTAL APPARATUS
1.1 Force and Torque measurements
1.1.1 Isometric custom-made chair
1.1.2 Isokinetic dynamometer
1.1.3 Customized cycle-ergometer
1.3.1 Femoral nerve magnetic stimulation
1.3.2 Peripheral Nerve Electrical Stimulation
1.4 Physical activity
2. FATIGUING AND FUNCTIONAL TASKS
2.1 Fatiguing tasks
2.1.1 The isometric quadriceps intermittent fatigue test
2.1.2 The isometric body-weight based QIF test
2.1.3 The concentric body-weight based QIF test
2.1.4 The body-weight based QIF test on the customized cyclo-ergometer
2.2 Functional capacity assessment
3. ADDITIONAL DATA
1. STUDY 1 ASSOCIATION BETWEEN PHYSICAL ACTIVITY, QUADRICEPS MUSCLE PERFORMANCE AND BIOLOGICAL CHARACTERISTICS OF VERY OLD MEN AND WOMEN
2. STUDY 2 AGE-RELATED DIFFERENCES IN PERFORMANCE AND FATIGABILITY DURING AN ISOMETRIC QUADRICEPS INTERMITTENT FATIGUE TEST
3. STUDY 3 EFFECTS OF OLD AND VERY OLD AGE ON PERFORMANCE AND FATIGABILITY DURING ISOMETRIC, CONCENTRIC AND CYCLING FATIGUING TASKS IN MEN
DISCUSSION AND PERSPECTIVES