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The present study investigated motor unit (MU) loss in a murine model of familial amyotrophic lateral sclerosis (ALS). The fast-twitch tibialis anterior (TA) and medial gastrocnemius (MG) muscles of transgenic SOD1G93A and SOD1 WT mice were studied during the presymptomatic phase of disease progression at 60 days of age. Whole muscle maximum isometric twitch and tetanic forces were 80% lower (P < 0.01) in the TA muscles of SOD1 G93A compared to SOD1 WT mice. Enumeration of total MU numbers within TA muscles showed a 60% reduction (P < 0.01) within SOD1 G93A mice (38 ± 7) compared with SOD1 WT controls (95 ± 12); this was attributed to a lower proportion of the most forceful fast-fatigable (FF) MU in SOD1 G93A mice, as seen by a significant (P < 0.01) leftward shift in the cumulative frequency histogram of single MU forces. Similar patterns of MU loss and corresponding decreases in isometric twitch force were observed in the MG. Immunocytochemical analyses of the entire cross-sectional area (CSA) of serial sections of TA muscles stained with anti-neural cell adhesion molecule (NCAM) and various monoclonal antibodies for myosin heavy chain (MHC) isoforms showed respective 65% (P < 0.01) and 28% (P < 0.05) decreases in the number of innervated IIB and IID/X muscle fibres in SOD1 G93A , which paralleled the 60% decrease (P < 0.01) in the force generating capacity of individual fibres. The loss of fast MUs was partially compensated by activity-dependent fast-to-slower fibre type transitions, as determined by increases (P < 0.04) in the CSA and proportion of IIA fibres (from 4% to 14%) and IID/X fibres (from 31% to 39%), and decreases (P < 0.001) in the CSA and proportion of type IIB fibres (from 65% to 44%). We conclude that preferential loss of IIB fibres is incomplete at 60 days of age, and is consistent with a selective albeit gradual loss of FF MUs that is not fully compensated by sprouting of the remaining motoneurons that innervate type IIA or IID/X muscle fibres. Our findings indicate that disease progression in fast-twitch muscles of SOD1 G93A

Motor unit (MU) enlargement by sprouting is an important compensatory mechanism for loss of functional MUs during normal aging and neuromuscular disease. Perisynaptic Schwann cells at neuromuscular junctions extend processes that bridge between denervated and reinnervated endplates, and guide axonal sprouts to reinnervate the denervated endplates. In a rat model of partial denervation, high levels of daily neuromuscular activity have been shown to inhibit the outgrowth of sprouts by preventing Schwann cell bridging. In this review, we consider (1) the relative roles of increasing levels of oxidative stress and neuromuscular activity to the destabilization of neuromuscular junctions with age and disease, and (2) how a progressive increase in the neuromuscular activity of declining numbers of functional MUs contributes to the progressive failure of adaptive sprouting and, in turn, to the progressive muscle weakness in the motoneuron diseases of post-polio syndrome and amyotrophic lateral sclerosis. We conclude that there is a time-related progression of MU loss, adaptive sprouting followed by maladaptive sprouting, and continuing recession of terminals during normal aging. The progression is accelerated in motoneuron disease, progressing more rapidly in the post-polio syndrome after prolonged denervation and extremely rapidly in ALS.

; for the SpecTRA Study Group IMPORTANCE Sex differences have been described in the presentation, care, and outcomes among people with acute ischemic strokes, but these differences are less understood for minor ischemic cerebrovascular events. The present study hypothesized that, compared with men, women are more likely to report nonfocal symptoms and to receive a stroke mimic diagnosis. OBJECTIVE To evaluate sex differences in the symptoms, diagnoses, and outcomes of patients with acute transient or minor neurologic events. DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study of patients with minor ischemic cerebrovascular events or stroke mimics enrolled at multicenter academic emergency departments in Canada between December 2013 and March 2017 and followed up for 90 days is a substudy of SpecTRA (Spectrometry for Transient Ischemic Attack Rapid Assessment). In total, 1729 consecutive consenting patients with acute transient or minor neurologic symptoms were referred for neurologic evaluation; 66 patients were excluded for protocol violation (n = 46) or diagnosis of transient global amnesia (n = 20). EXPOSURES The main exposure was female or male sex. MAIN OUTCOMES AND MEASURES The main outcome was the clinical diagnosis (cerebral ischemia vs stroke mimic). Secondary outcomes were 90-day stroke recurrence and 90-day composite outcome of stroke, myocardial infarction, or death. The association between presenting symptoms (focal vs nonfocal) and clinical diagnosis was also assessed. Research hypotheses were formulated after data collection. RESULTS Of 1648 patients included, 770 (46.7%) were women, the median (interquartile range) age was 70 (59-80) years, 1509 patients (91.6%) underwent brain magnetic resonance imaging, and 1582 patients (96.0%) completed the 90-day follow-up. Women (522 of 770 [67.8%]) were less likely than men (674 of 878 [76.8%]) to receive a diagnosis of cerebral ischemia (adjusted risk ratio [aRR], 0.88; 95% CI, 0.82-0.95), but the 90-day stroke recurrence outcome (aRR, 0.90; 95% CI, 0.48-1.66) and 90-day composite outcome (aRR, 0.86; 95% CI, 0.54-1.32) were similar for men and women. No significant sex differences were found for presenting symptoms. Compared with patients with no focal neurologic symptoms, those with focal and nonfocal symptoms were more likely to receive a diagnosis of cerebral ischemia (aRR, 1.28; 95% CI, 1.15-1.39), but the risk was highest among patients with focal symptoms only (aRR, 1.45; 95% CI, 1.34-1.53). Sex did not modify these associations. CONCLUSIONS AND RELEVANCE The results of the present study suggest that, despite similar presenting symptoms among men and women, women may be more likely to receive a diagnosis of stroke mimic, but they may not have a lower risk than men of subsequent vascular events, indicating potentially missed opportunities for prevention of vascular events among women.

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Major LA, Hegedus J, Weber DJ, Gordon T, Jones KE. Method for counting motor units in mice and validation using a mathematical model. J Neurophysiol 97: 1846 -1856, 2007. First published December 6, 2006; doi:10.1152/jn.00904.2006. Weakness and atrophy are clinical signs that accompany muscle denervation resulting from motor neuron disease, peripheral neuropathies, and injury. Advances in our understanding of the genetics and molecular biology of these disorders have led to the development of therapeutic alternatives designed to slow denervation and promote reinnervation. Preclinical in vitro research gave rise to the need of a method for measuring the effects in animal models. Our goal was to develop an efficient method to determine the number of motor neurons making functional connections to muscle in a transgenic mouse model of amyotrophic lateral sclerosis (ALS). We developed a novel protocol for motor unit number estimation (MUNE) using incremental stimulation. The method involves analysis of twitch waveforms using a new software program, ITS-MUNE, designed for interactive calculation of motor unit number. The method was validated by testing simulated twitch data from a mathematical model of the neuromuscular system. Computer simulations followed the same stimulus-response protocol and produced waveform data that were indistinguishable from experiments. We show that our MUNE protocol is valid, with high precision and small bias across a wide range of motor unit numbers. The method is especially useful for large muscle groups where MUNE could not be done using manual methods. The results are reproducible across naïve and expert analysts, making it suitable for easy implementation. The ITS-MUNE analysis method has the potential to quantitatively measure the progression of motor neuron diseases and therefore the efficacy of treatments designed to alleviate pathologic processes of muscle denervation.

We examined whether there are gender differences in the progressive loss of functional motor units in SOD1(G93A) transgenic mice. Isometric muscle and motor unit twitch contractions were recorded in fast- and slow-twitch muscles in response to stimulation of the sciatic nerve. Using a modified motor unit number estimation technique (ITS-MUNE), we found that motor unit numbers declined rapidly from 40 to 90 days of age during the asymptomatic phase of ALS in fast- but not slow-twitch hindlimb muscles of both male and female mice. There was a corresponding decline in twitch and tetanic contractile forces of the fast-twitch muscles. Gender did not affect the progressive loss of motor units and associated decline in force production. We conclude that gender does not alter progressive, muscle-specific motor unit loss in ALS, even though gender does influence disease onset.