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Chronic musculoskeletal (CMSK) pain associated with musculoskeletal disorders like low back pain or neck pain are the leading causes of disability. While CMSK pain has the potential to negatively influence motor learning, there is limited research to understand the impact of CMSK on motor learning. In order to examine differences in motor learning between individuals with and without CMSK we modified a serial reaction time task to assess motor learning of a repetitive reaching task. The paradigm was used to assess both explicit and implicit motor learning. In a cross-sectional study design, seventeen participants with chronic neck pain (CNP) (5 males) and 21 controls (8 males) were recruited. In addition, physical, cognitive, sensorimotor, disability and pain assessments were used to examine differences between individuals with and without CNP. All participants with CNP were categorized as having mild disability. There was no difference in cognitive assessments and minimal differences in physical measures between groups. Examining motor learning, groups with and without CNP demonstrated similar outcomes in both explicit and implicit motor learning. There was one notable performance difference between groups in the reaching task, the group with CNP demonstrated slower reaching movements outward and inward during blocks without explicit information. This may suggest a cautious approach to movement with reduced explicit information. Findings from this study provide insight on motor learning in individuals with mildly-disabling CNP, further research is necessary to examine how instruction can impact peak performance in people with CMSK pain.

Sarcopenia and frailty are highly prevalent in older individuals, increasing the risk of disability and loss of independence. High intensity interval training (HIIT) may provide a robust intervention for both sarcopenia and frailty by achieving both strength and endurance benefits with lower time commitments than other exercise regimens. To better understand the impacts of HIIT during aging, we compared 24-month-old C57BL/6J sedentary mice with those that were administered 10-minute uphill treadmill HIIT sessions three times per week over 16 weeks. Baseline and end point assessments included body composition, physical performance, and frailty based on criteria from the Fried physical frailty scale. HIIT-trained mice demonstrated dramatic improvement in grip strength (HIIT 10.9% vs -3.9% in sedentary mice), treadmill endurance (32.6% vs -2.0%), and gait speed (107.0% vs 39.0%). Muscles from HIIT mice also exhibited greater mass, larger fiber size, and an increase in mitochondrial biomass. Furthermore, HIIT exercise led to a dramatic reduction in frailty scores in five of six mice that were frail or prefrail at baseline, with four ultimately becoming nonfrail. The uphill treadmill HIIT exercise sessions were well tolerated by aged mice and led to performance gains, improvement in underlying muscle physiology, and reduction in frailty.

At birth, each mammalian skeletal muscle fiber is innervated by multiple motor neurons, but in a few weeks, all but one of those axons retracts (Redfern, 1970) and differential activity between inputs controls this phenomenon (Personius and Balice-Gordon, 2001; Sanes and Lichtman, 2001; Personius et al., 2007; Favero et al., 2012). Acetylcholine, the primary neuromuscular transmitter, has long been presumed to mediate this activity-dependent process (O9Brien et al., 1978), but glutamatergic transmission also occurs at the neuromuscular junction (Berger et al., 1995; Grozdanovic and Gossrau, 1998; Mays et al., 2009). To test the role of neuromuscular NMDA receptors, we assessed their contribution to muscle calcium fluxes in mice and tested whether they influence removal of excess innervation at the end plate. Developmental synapse pruning was slowed by reduction of NMDA receptor activation or expression and by reduction of glutamate production. Conversely, pruning is accelerated by application of exogenous NMDA. We also found that NMDA induced increased muscle calcium only during the first 2 postnatal weeks. Therefore, neuromuscular NMDA receptors play previously unsuspected roles in neuromuscular activity and synaptic pruning during development. SIGNIFICANCE STATEMENT In normal adult muscle, each muscle fiber is innervated by a single axon, but at birth, fibers are multiply innervated. Elimination of excess connections requires neural activity; because the neuromuscular junction (NMJ) is a cholinergic synapse, acetylcholine has been assumed to be the critical mediator of activity. However, glutamate receptors are also expressed at the NMJ. We found that axon removal in mice is slowed by pharmacological and molecular manipulations that decrease signaling through neuromuscular NMDA receptors, whereas application of exogenous NMDA at the NMJ accelerates synapse elimination and increases muscle calcium levels during the first 2 postnatal weeks. Therefore, neuromuscular NMDA receptors play previously unsuspected roles in neuromuscular activity and elimination of excess synaptic input during development.

Introduction Duchenne muscular dystrophy (DMD) is caused by loss of the structural protein, dystrophin, resulting in muscle fragility. Muscle stem cell (MuSC) transplantation is a potential therapy for DMD. It is unknown whether donor-derived muscle fibers are structurally innervated. Methods Green fluorescent protein (GFP)-expressing MuSCs were transplanted into the tibials anterior of adult dystrophic mdx/mTR mice. Three weeks later the neuromuscular junction was labeled by immunohistochemistry. Results The percent overlap between pre- and postsynaptic immunolabeling was greater in donor-derived GFP(+) myofibers, and fewer GFP(+) myofibers were identified as denervated compared with control GFP(-) fibers (P = 0.001 and 0.03). GFP(+) fibers also demonstrated acetylcholine receptor fragmentation and expanded endplate area, indicators of muscle reinnervation (P = 0.008 and 0.033). Conclusion It is unclear whether GFP(+) fibers are a result of de novo synthesis or fusion with damaged endogenous fibers. Either way, donor-derived fibers demonstrate clear histological innervation. Muscle Nerve 54: 763-768, 2016.

Introduction: Full-length tyrosine kinase B (TrkB.FL) and truncated TrkB (TrkB.t1) receptors are colocalized with acetylcholine receptors (AChRs) at the neuromuscular junction. We have recently shown that reduced TrkB expression leads to age-related alterations in AChR structure, neurotransmission failure, and muscle weakness. Methods: We investigated whether TrkB expression is reduced in the soleus muscle during aging. Results: TrkB protein expression was decreased in senescent (24-month-old) compared with 3–12-month-old mice. Loss of TrkB expression was concurrent with age-related changes in AChR morphology. Changes in mRNA levels did not correlate with protein expression, because TrkB.FL copy number was increased in the senescent soleus. No change was seen in TrkB.t1 levels. Conclusions: The results suggest that reduced TrkB expression during aging may result from reduced TrkB.FL mRNA translation or increased TrkB protein turnover. Thus, maintaining adequate TrkB signaling is a potential therapeutic tool to improve muscle function during senescence. Muscle Nerve 47: 532–538, 2013

There is no consensus about whether making muscles abnormally large by reducing myostatin activity affects force-generating capacity or the ability to perform activities requiring muscular endurance. We therefore examined grip force, contractile properties of extensor digitorum longus (EDL) muscles, and voluntary wheel running in mice in which myostatin was depleted after normal muscle development. Cre recombinase activity was induced to knock out exon 3 of the myostatin gene in 4-mo-old mice in which this exon was flanked by loxP sequences (Mstn[f/f]). Control mice with normal myostatin genes (Mstn[w/w]) received the same Cre-activating treatment. Myostatin depletion increased the mass of all muscles that were examined (gastrocnemius, quadriceps, tibialis anterior, EDL, soleus, triceps) by ∼20–40%. Grip force, measured multiple times 2–22 wk after myostatin knockout, was not consistently greater in the myostatin-deficient mice. EDL contractile properties were determined 7–13 mo after myostatin knockout. Twitch force tended to be greater in myostatin-deficient muscles (+24%; P = 0.09), whereas tetanic force was not consistently elevated (mean +11%; P = 0.36), even though EDL mass was greater than normal in all myostatin-deficient mice (mean +36%; P < 0.001). The force deficit induced by eccentric contractions was approximately twofold greater in myostatin-deficient than in normal EDL muscles (31% vs. 16% after five eccentric contractions; P = 0.02). Myostatin-deficient mice ran 19% less distance ( P < 0.01) than control mice during the 12 wk following myostatin depletion, primarily because of fewer running bouts per night rather than diminished running speed or bout duration. Reduced specific tension (ratio of force to mass) and reduced running have been observed after muscle hypertrophy was induced by other means, suggesting that they are characteristics generally associated with abnormally large muscles rather than unique effects of myostatin deficiency.

Mammalian neuromuscular synapses undergo an activity-dependent competitive transition from multiple to single innervation during postnatal life. The presence of temporally correlated motor neuron activity, which, in part, is controlled by gap junctional coupling within the spinal cord, appears to modulate synapse elimination. Postnatal injection of dizocilpine maleate (MK801), a specific NMDA antagonist, has been shown to maintain gap junctional coupling among motor neurons. Thus, we tested the hypothesis that MK801 would maintain correlated motor neuron activity and delay postnatal synapse elimination. Temporally correlated motor neuron activity, which is normally lost during the second postnatal week, was maintained and synaptic competition was delayed by several days in 2-week-old mice injected daily with MK801. MK801 appears to modulate motor neuron activity patterns through enhancing mRNA expression of multiple connexins within the spinal cord and delaying motor neuron growth. Our results suggest that MK801 injection preserves correlated neural activity via both synaptic mechanisms and maintenance of gap junctional coupling among neurons within the spinal cord, ultimately delaying synapse elimination.

Skeletal muscles in mdx mice exhibit differential degrees of pathological changes and fibrosis. The purpose of this study was to examine differences in various indices of collagen metabolism in skeletal muscles with widely different functions and activity profiles in mdx mice, and to determine whether pirfenidone would attenuate the development of fibrosis. Mice in the pirfenidone group were orally fed pirfenidone (500 mg/kg) daily for 4 weeks. Marked differences were noted in hydroxyproline concentration between muscles, which could not be explained solely by the level of type I collagen and transforming growth factor-β1 (TGF-β1) mRNA. In normal mice, matrix metalloproteinase (MMP)-2 mRNA was significantly higher in the gastrocnemius than in the diaphragm or genioglossus muscles, suggesting that collagen degradation plays an important role in regulating collagen accretion in skeletal muscle. In mdx mice, the levels of both MMP-2 and MMP-9 mRNA were significantly elevated relative to control, although the response was muscle specific. Pirfenidone treatment resulted in a significant reduction in the level of hydroxyproline concentration across all muscles, although the effect was small. Results from this study reveal intrinsic dissimilarities in collagen metabolism between functionally different skeletal muscles. Moreover, the pharmacological use of pirfenidone may be beneficial in preventing fibrosis in muscular dystrophy. Muscle Nerve, 2006

Loss of Muscleblind-like 1 (Mbnl1) is known to alter Clc-1 splicing to result in myotonia. Mbnl1ΔE3/ΔE3/Mbnl3ΔE2 mice, depleted of Mbnl1 and Mbnl3, demonstrate a profound enhancement of myotonia and an increase in the number of muscle fibers with very low Clc-1 currents, where gClmax values approach ~ 1 mS/cm2, with the absence of a further enhancement in Clc-1 splice errors, alterations in polyA site selection or Clc-1 localization. Significantly, Mbnl1ΔE3/ΔE3/Mbnl3ΔE2 muscles demonstrate an aberrant accumulation of Clc-1 RNA on monosomes and on the first polysomes. Mbnl1 and Mbnl3 bind Clc-1 RNA and both proteins bind Hsp70 and eEF1A, with these associations being reduced in the presence of RNA. Thus binding of Mbnl1 and Mbnl3 to Clc-1 mRNA engaged with ribosomes can facilitate an increase in the local concentration of Hsp70 and eEF1A to assist Clc-1 translation. Dual depletion of Mbnl1 and Mbnl3 therefore initiates both Clc-1 splice errors and translation defects to synergistically enhance myotonia. As the HSALR model for myotonic dystrophy (DM1) shows similar Clc-1 defects, this study demonstrates that both splice errors and translation defects are required for DM1 pathology to manifest. Research in context Research in context: Myotonic Dystrophy type 1 (DM1) is a dominant disorder resulting from the expression of expanded CUG repeat RNA, which aberrantly sequesters and inactivates the muscleblind-like (MBNL) family of proteins. In mice, inactivation of Mbnl1 is known to alter Clc-1 splicing to result in myotonia. We demonstrate that concurrent depletion of Mbnl1 and Mbnl3 results in a synergistic enhancement of myotonia, with an increase in muscle fibers showing low chloride currents. The observed synergism results from the aberrant accumulation of Clc-1 mRNA on monosomes and the first polysomes. This translation error reflects the ability of Mbnl1 and Mbnl3 to act as adaptors that recruit Hsp70 and eEF1A to the Clc-1 mRNA engaged with ribosomes, to facilitate translation. Thus our study demonstrates that Clc-1 RNA translation defects work coordinately with Clc-1 splice errors to synergistically enhance myotonia in mice lacking Mbnl1 and Mbnl3., Highlights • Mbnl 1 & 3 loss enhances myotonia and increases fibers with low chloride currents. • Clc-1 RNA increase in lighter polysome fractions results in low chloride currents. • Mbnl 1 & 3 interact with Hsp70 and eEF1A in an RNA moderated manner. • Mbnl 1 & 3 recruitment of Hsp70 and eEF1A to Clc-1 RNA facilitates translation. • The HSALR DM1 mouse model shows similar Clc-1 RNA translation defects.

Recent data support an important role for vitamin D in respiratory health. We tested the hypothesis that dietary vitamin D3 (VD3) intake modulates diaphragm (DIA) strength. Four-week-old female A/J mice ( n = 10/group) were randomized to receive diets containing 100 IU VD3/kg (low), 1,000 IU VD3/kg (reference), or 10,000 IU VD3/kg (pharmacologic). After 6 wk of dietary intervention, plasma 25-hydroxyvitamin D3 (25D3) levels, DIA and extensor digitorum longus (EDL) in vitro contractile properties, and fiber cross-sectional area (CSA) were measured. Myosin heavy chain (MHC) composition and Akt/Foxo3A growth signaling were studied in the DIA and tibialis anterior. Mice fed the low, reference, and pharmacologic diets had average 25D3 levels of 7, 21, and 59 ng/ml, respectively. Maximal DIA force, twitch force, and fiber CSA were reduced 26%, 28%, and 10% ( P < 0.01), respectively, in mice receiving the low-VD3 diet compared with the reference and pharmacologic diets. EDL force parameters were unaltered by diet. Effects of VD3 intake on DIA force were not observed in mice that began dietary intervention at 12 wk of age. VD3 intake did not alter the MHC composition of the DIA, indicating that decreases in force and CSA in young mice were not due to a switch in fiber type. Paradoxically, low VD3 intake was associated with activation of anabolic signaling in muscle (hyperphosphorylation of Akt and Foxo3A and decreased expression of autophagy marker LC3). These studies identify a potential role of dietary VD3 in regulating DIA development and insulin sensitivity.

Loss of specific muscle force and evidence of myopathy are present in the diaphragm of mdx mice by 4 weeks of age. The neuromuscular junction of dystrophic muscle also shows structural abnormalities at this age. Whether these structural alterations result in neural transmission abnormalities is currently unclear, particularly at physiological firing frequencies. Thus, we investigated the extent of neurotransmission variability and failure during 35 and 100 Hz stimulation in the diaphragm of 6 to 8-month-old mdx mice in comparison to age-matched controls. Neurotransmission failure was similar across groups at both stimulation frequencies, despite the presence of disrupted post-synaptic acetylcholine receptors (AChRs). Neural transmission variability, however, measured by comparing variation in force production during direct muscle stimulation compared to variation in force production during phrenic nerve stimulation was significantly greater in dystrophic muscle. Together, these results suggest that neurotransmission is maintained at physiologic firing frequencies in dystrophic muscle, but the precision of neurotransmission is attenuated. A reduced density of functional AChRs likely underlies the increase in neurotransmission variability.

The diaphragm muscle of the mdx mouse is a model system of Duchenne muscular dystrophy, since it completely lacks dystrophin and shows severe fiber necrosis and loss of specific muscle force by 4-6 weeks of age. Changes in neuromuscular junction structure also become apparent around 4 weeks including postsynaptic acetylcholine receptor declustering, loss of postsynaptic junctional folds, abnormally complex presynaptic nerve terminals, and muscle fiber denervation. Normally, terminal Schwann cells (TSCs) cap both nerve terminals and acetylcholine receptors at the neuromuscular junction, and play a crucial role in regeneration of motor axons following muscle denervation by guiding axons to grow from innervated junctions to nearby denervated junctions. However, their role in restoring innervation in dystrophic muscle is unknown. We now show that TSCs fail to cap fully the neuromuscular junction in dystrophic muscle; TSCs extend processes, but the organization of these extensions is abnormal. TSC processes of dystrophic muscle do not form bridges from denervated fibers to nearby innervated endplates, but appear to be directed away from these endplates. Adequate signaling for TSC reactivity is present, since significant muscle fiber denervation and acetylcholine receptor declustering are present. Thus, significant structural denervation is present in the diaphragm of mdx mice and the ability of TSCs to form bridges between adjacent endplates to guide reinnervation of muscle fibers is impaired, possibly attenuating the ability of dystrophic muscle to recover from denervation and ultimately leading to muscle weakness.

Experience-dependent editing shapes synaptic connections throughout the developing nervous system, but the underlying cellular mechanisms remain poorly understood. A useful model synapse for addressing these mechanisms is the neuromuscular junction, the connection between spinal motor neurons and skeletal muscle fibers. Here the authors review current ideas about the role of activity in editing neuromuscular synaptic connections. A variety of new tools are being used to address some unanswered questions in vivo and in vitro. Understanding activity-dependent plasticity at developing neuromuscular synapses may reveal how neural circuits in the central nervous system are altered by experience throughout life.

During late stages of neural development, synaptic circuitry is edited by neural activity. At neuromuscular synapses, the transition from multiple to single innervation is modulated by the relative pattern of activity among inputs competing for innervation of the same muscle fiber. While experimental perturbations of activity result in marked changes in the timing of neuromuscular synaptic competition, little is known about the patterns of activity present during normal development. Here, we report the temporal patterning of motor unit activity in the soleus muscle of awake, behaving neonatal mice, and that patterning is modulated by gap-junctional coupling. Our work suggests that neuromuscular synaptic competition is modulated by surprisingly low levels of activity and may be triggered by the disappearance of temporally correlated activity among inputs competing for innervation of the same muscle fiber.

Full-length tyrosine kinase B (TrkB.FL) and truncated TrkB (TrkB.t1) receptors are colocalized with acetylcholine receptors (AChRs) at the neuromuscular junction. We have recently shown that reduced TrkB expression leads to age-related alterations in AChR structure, neurotransmission failure, and muscle weakness.We investigated whether TrkB expression is reduced in the soleus muscle during aging.TrkB protein expression was decreased in senescent (24-month-old) compared with 3-12-month-old mice. Loss of TrkB expression was concurrent with age-related changes in AChR morphology. Changes in mRNA levels did not correlate with protein expression, because TrkB.FL copy number was increased in the senescent soleus. No change was seen in TrkB.t1 levels.The results suggest that reduced TrkB expression during aging may result from reduced TrkB.FL mRNA translation or increased TrkB protein turnover. Thus, maintaining adequate TrkB signaling is a potential therapeutic tool to improve muscle function during senescence.

Background and Purpose. The natural history of facioscapulohumeral muscular dystrophy (FSHD) has not been studied prospectively. Knowledge of the natural progression of any disease provides essential information for the design of clinical trials. We present a protocol for the study of the natural history of FSHD using quantitative muscle testing (QMT), manual muscle testing (MMT), and functional testing. Subjects. Thirty-two persons with FSHD (mean age=36.1 years, SD=9.6, range=17–49) and 32 age- and gender-matched volunteer controls (mean age=35.8 years, SD=8.0, range=23–50) served as subjects. Methods. Using standardized testing procedures, we examined intrarater reliability of the MMT, QMT, and functional testing measurements in both groups. We also examined interrater reliability in 7 subjects with FSHD. Eighteen muscle groups were tested for each subject using QMT and MMT. Results. Intraclass correlation coefficient (ICC) values ranged from .86 to .99 for intrarater reliability and from .86 to .99 for interrater reliability of QMT measurements. Weighted kappa values of .81 to .98 for intrarater reliability and .50 to 1.00 for interrater reliability were obtained for MMT measurements. Intrarater ICCs for various functional testing measures ranged from .60 to .97. In addition, the comparability of the two QMT machines used in the study was demonstrated by testing the same set of volunteer controls on each machine's linear force transducer (ICC=.89–.98). Conclusion and Discussion. We conclude that this standardized testing protocol produces reliable measurements of muscle strength and functional ability in subjects with FSHD.

Acute blockade of signaling through the tyrosine kinase receptor B (TrkB) attenuates neuromuscular transmission and fragments postsynaptic acetylcholine receptors (AChRs) in adult mice, suggesting that TrkB signaling is a key regulator of neuromuscular function. Using immunohistochemical, histological, and in vitro muscle contractile techniques, we tested the hypothesis that constitutively reduced TrkB expression would disrupt neuromuscular pre- and postsynaptic structure, neurotransmission, muscle fiber size, and muscle function in the soleus muscle of 6- to 8-mo-old TrkB+/− mice compared with age-matched littermates. Age-like expansion of postsynaptic AChR area, AChR fragmentation, and denervation was observed in TrkB+/− mice similar to that found in 24-mo-old wild-type mice. Neurotransmission failure was increased in TrkB+/− mice, suggesting that these morphologic changes were sufficient to alter synaptic function. Reduced TrkB expression resulted in decreased muscle strength and fiber cross-sectional area. Immunohistochemical and muscle retrograde labeling experiments show that motor neuron number and size are unaffected in TrkB+/− mice. These results suggest that TrkB- signaling at the neuromuscular junction plays a role in synaptic stabilization, neurotransmission, and muscle function and may impact the aging process of sarcopenia.

Activity-dependent specification of neuronal architecture during early postnatal life is essential for refining the precision of communication between neurons. In the spinal cord under normal circumstances, the AMPA receptor subunit GluR1 is expressed at high levels by motor neurons and surrounding interneurons during this critical developmental period, although the role it plays in circuit formation and locomotor behavior is unknown. Here, we show that GluR1 promotes dendrite growth in a non-cell-autonomous mannerin vitroandin vivo. The mal-development of motor neuron dendrites is associated with changes in the pattern of interneuronal connectivity within the segmental spinal cord and defects in strength and endurance. Transgenic expression of GluR1 in adult motor neurons leads to dendrite remodeling and supernormal locomotor function. GluR1 expression by neurons within the segmental spinal cord plays an essential role in formation of the neural network that underlies normal motor behavior.

During late embryonic and early postnatal life, neuromuscular junctions undergo synapse elimination that is modulated by patterns of motor neuron activity. Here, we test the hypothesis that reduced spinal neuron gap junctional coupling decreases temporally correlated motor neuron activity that, in turn, modulates neuromuscular synapse elimination, by using mutant mice lacking connexin 40 (Cx40), a developmentally regulated gap junction protein expressed in motor and other spinal neurons. In Cx40 −/− mice, electrical coupling among lumbar motor neurons, measured by whole-cell recordings, was reduced, and single motor unit recordings in awake, behaving neonates showed that temporally correlated motor neuron activity was also reduced. Immunostaining and intracellular recording showed that the neuromuscular synapse elimination was accelerated in muscles from Cx40 −/− mice compared with WT littermates. Our work shows that gap junctional coupling modulates neuronal activity patterns that, in turn, mediate synaptic competition, a process that shapes synaptic circuitry in the developing brain.

Myotonic dystrophy (DM1) is an autosomal-dominant multisystem disease characterized by progressive skeletal muscle weakness, myotonia, cataracts, cardiac arrhythmias, mild mental retardation, and endocrinopathies. Heterozygous loss of SIX5 in mice causes cataracts and cardiac conduction disease, and homozygous loss also leads to sterility and decreased testicular mass, reminiscent of DM1 in humans. The effect of SIX5 deficiency in muscle is unknown. In this study, we found that muscle contractile properties, electromyographic insertional activity, and muscle histology were normal in SIX5 deficient mice. The implications of these findings for the pathogenesis of DM1 are discussed.

Nerve and Muscle, Third Edition, Richard D. Keynes and David J. Aidley, Cambridge: Cambridge University Press (2001). 192 pp, $59.95 hardback, $19.95 paperbackA concise and engaging summary of a large body of work on the electrical language of the nervous system, the third edition of Nerve and Muscle by Keynes and Aidley makes this complex literature accessible for students and professionals.For more than 160 years, muscle and its neural innervation have served as model systems for studies of electrical excitability as well as cellular and synaptic structure and function. Since the first descriptions of large nerve endings on striated muscle fibers in the arthropod Milnesium tardigradum by Doyere in 1840, the experimental accessibility of presynaptic motor neurons and postsynaptic muscle fibers has been largely unmatched. Descriptions of synaptic structure in the late 1800s and early 1900s were followed by studies of the mechanisms of neurotransmitter release in the 1950s, excitation-contraction coupling in muscle fibers in the 1970s, and regulation of gene expression by innervation and activity over the last two decades. Molecular and genetic approaches have been used to understand the mechanisms of each of these processes and have broken new ground in the understanding and treatment of nerve and muscle diseases, for example, the dystrophinopathies. Many of these studies laid a firm foundation for work on neuronal structure and function in the relatively less accessible CNS.In the third edition of their classic short textbook, Nerve and Muscle (Figure 1(Figure 1), published this year by Cambridge University Press, Richard Darwin Keynes and the late David John Aidley have provided a highly readable primer that describes the fundamental principles underlying nerve and muscle function. The authors are uniquely positioned to offer a historical as well as personal perspective of seminal experiments on electrical excitability of neurons and muscle fibers. Keynes performed studies of action potential generation and propagation with Hodgkin, among others, and was the first to monitor ionic movements during action potential propagation in giant axons from cephalopods, using radioactive sodium and potassium (Keynes, 1951, J. Physiol. 114, 151–182). Aidley conducted groundbreaking work on the role of calcium in excitation-contraction coupling in insect muscle and spent much of his career understanding the biophysical and regulatory aspects of this process.Figure 1View Large Image | View Hi-Res Image | Download PowerPoint SlideThe authors do an admirable job of integrating this classic work with more recent studies, covering the mechanisms underlying action potential generation and propagation, the resting potential, and the structure and function of voltage- and ligand-gated ion channels. This edition includes insights derived from molecular studies, most notably, the mechanisms underlying channel ion selectivity and voltage gating. Neuromuscular synaptic transmission is compared to that at CNS synapses, focusing on excitatory and inhibitory inputs to motor neurons. Muscle anatomy, excitation-contraction coupling, and exercise-induced modulation of function in striated, smooth, and cardiac muscle is covered in three short chapters. Work on muscle ultrastructure is nicely but briefly married to molecular insights into contractile function.By concisely summarizing a huge body of work, the authors make this literature accessible to the nonspecialist or to the undergraduate just beginning to study neuroscience. This is the singular strength of this text; few, if any, comparable efforts have been targeted to such an audience. This strength, however, is also a weakness, in that it limits the text's appeal to advanced students or practicing neuroscientists wanting more comprehensive coverage of the electrical language of neurons. Kandel et al.'s Principles of Neural Science (McGraw Hill Press), Nichols et al.'s From Neuron to Brain (Sinauer Press), or Aidley's Physiology of Excitable Cells (Cambridge University Press) are targeted to this latter audience. The illustrations in Keynes and Aidley leave something to be desired; they are rudimentary and not well integrated into the text. In an era of animated, multicolor PowerPoint presentations, they seem rather uninspired as didactic tools. The brevity of the legends limits their usefulness in providing information that amplifies that presented in the main text. However, the writing is extraordinary—clear, beautifully constructed descriptions of experiments that lead the reader naturally to the major insights derived from the work. The chapter describing membrane permeability changes during the action potential and the sodium hypothesis put forth by Hodgkin and Katz in 1949 (Hodgkin and Katz, 1949, J. Physiol. 108, 37–77) is a particularly good example of this, incorporating simple illustrations, some basic mathematical concepts, and engaging prose. Authors who attempt to provide more experimental insights often sacrifice clarity, and this can blunt understanding of some fundamentally important work. Students approaching this literature for the first time will realize the true “potential” of this little gem of a text.