Sex matters in neuromuscular control

Abstract

In this issue, Guo and colleagues1 provide key insights into human neuromuscular control: humans of different sexes utilize different strategies for motor unit recruitment and firing rate, as shown during submaximal knee extension. Motor units, the quantal elements for all movement, are select sets of muscle fibers innervated by a single motoneuron.2 Spike times of motor unit firing instances recorded from the muscle provide information about the discharge of individual motoneurons; the final common pathway for all motor behavior.3 The central nervous system controls force output by recruiting motor units, and modulating firing rates, as shown in historical studies.4 Recruitment typically follows the size principle,5 where progressively larger, faster and stronger motor units are recruited with increases in force output. In many of the pioneering human physiological studies, the term “in man” was used to differentiate their findings from those obtained from non-human animal preparations. Its original use was likely not intended to indicate exclusively males, but rather humans of either sex. While over the years this term has been lost in favor of more inclusive terminology, physiological studies claiming to represent all humans have not sufficiently included both biological sexes. Current demographics in biological studies of both human and non-human animal models, including neurophysiology, have a male to female ratio of 5.8–1.6 Because of this, the field has generally assumed that many past findings equally apply to female physiology when in fact the samples were only, or predominantly, male. We now have a comprehensive understanding of physiology “in man”, despite the fact that we talk about it as an umbrella term for the physiology of all humans. In the field of motor control more generally, females have historically been excluded as study participants. However, this was not the case as the field emerged. As recently highlighted,7 the entire field of study on cross-education (ie training of only one limb causing improvements in strength or skill of the contralateral, untrained limb) was established by an investigation with exclusively female participants. In 1894, formative work from Edward Wheeler Scripture, Miss Theodate L. Smith and Miss Emily Brown showed this very concept.8 Miss Smith and Miss Brown, both co-authors and participants, were some of the first of thousands of participants who have helped move our field forward. Yet, in the 128 years since, the vast majority of participants in motor control studies have been male. As a scientific community, we must strive to reach a point where we are more broadly studying the physiology of all humans, which includes both sexes, since females and males each make up ~50% of humans. Even beyond the powerful prerogative of equity, from a clinical perspective, studying sex as a biological variable in motor control studies is warranted as neurological impairments differ in prevalence and progression between the sexes, and from a basic science standpoint because studies in recent decades have reported sex-differences in motoneuron behavior and fatigability. Guo and colleagues’ work1 is the latest to illustrate the need for equal inclusion of both sexes (males and females) when investigations aim to broadly study human neuromuscular control. As was explained previously, a fundamental principle of motor control is that in order to modulate forces, both the size of the recruited motor units and motor unit firing rate increase with progressive increases in muscular force. Guo and colleagues’ findings1 suggests this interplay between increasing motor unit size and firing rate differs between the sexes in the vastus lateralis. Specifically, when producing the same relative force as their male counterparts, females activate smaller motor units at higher firing rates. This is highly meaningful as it suggests females use a recruitment strategy that relies on higher firing rates of smaller motor units rather than recruiting larger motor units. It has been understood for some time that the recruitment strategies to increase force differ across various muscles, but this work1 reveals that the dynamics of firing rates of motor units along the size principle may also vary between the sexes. While studies such as this are an imperative first step for quantifying ways in which female physiology differs from males, as a field we must also begin to ask about the mechanisms and functional meanings underlying these differences. Many papers that discuss sex-difference analyses suggest the weak and largely unsubstantiated argument that the female menstrual cycle may introduce problematic variability in collected data. Sex hormones have extensive effects on many physiological systems throughout the human body and differ between the sexes. In eumenorrheic females, endogenous levels of estradiol and progesterone fluctuate regularly across the menstrual cycle and these fluctuations have been associated with aspects of motor control,9 including motoneuron firing rates and fatigue. At a more basic level, neurons throughout the body (ie throughout the cortex, brainstem, and spinal cord) contain estradiol and progesterone receptors, suggesting that fluctuating sex hormones may impact neuronal function, including that of motoneurons. One study to date has examined motor unit activity across the menstrual cycle, and showed fluctuations in firing behavior.10 These findings emphasize the fact that understanding female motoneuron behavior will require a full analysis of how hormonal cycles affect the physiology under study. However, in order to accurately determine whether hormonal cycles affect motor unit physiology, well-designed studies that include both females and males are paramount. The elegant work in the current issue by Guo et al1 is an exemplar for equitably creating a foundation for understanding female neuromuscular control that benefits all humans. We have no conflicts of interest to declare.

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