Symptom onset in amyotrophic lateral sclerosis (ALS) may occur in the muscles of the limbs (spinal onset) or those of the head and neck (bulbar onset). Most preclinical studies have focused on spinal symptoms, despite the prevalence of and increased morbidity and mortality associated with bulbar disease. We measured lick rhythm and tongue force to evaluate bulbar disease in the SOD1-G93A rat model of familial ALS. Body weight and grip strength were measured concomitantly. Testing spanned the early (maturation), middle (pre-symptomatic), and late (symptomatic and end-stage) phases of the disease. We measured a persistent tongue motility deficit that became apparent in the early phase of the disease, providing behavioral evidence of bulbar pathology. At end-stage, however, cytochrome oxidase (CO) activity was normal in the hypoglossal nucleus, and in the tongue, neuromuscular innervation, citrate synthase (CS) protein levels and activity, and uncoupling protein 3 (UCP3) protein levels remained unchanged. Interestingly, significant denervation and atrophy were evident in the end-stage sternomastoid muscle, providing peripheral anatomical evidence of bulbar pathology. Changes in body weight and grip strength occurred in the late phase of the disease. Extensive atrophy and denervation were observed in the end-stage gastrocnemius muscle. In contrast to our findings in the tongue, CS protein levels were decreased in the extensor digitorum longus (EDL) and soleus, although CS activity was maintained or increased. UCP3 protein was decreased also in the EDL. These data provide evidence of differential effects in muscles that were more or less affected by disease.

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease affecting upper and lower motor neurons. Symptom onset may occur in the muscles of the limbs (spinal onset) or those of the head and neck (bulbar onset). Bulbar involvement is particularly important in ALS as it is associated with increased morbidity and mortality. The purpose of this study was to characterize bulbar motor deficits in the SOD1-G93A mouse model of familial ALS. We measured orolingual motor function by placing thirsty mice in a customized operant chamber that allows for measurement of tongue force and lick rhythm as animals lick water from an isometric disc. Testing spanned the pre-symptomatic, symptomatic, and end-stage segments of the disease. Rotarod performance, fore-and hindlimb grip strength, and locomotor activity were also monitored regularly during this period. We found that spinal involvement was apparent first, with both fore-and hindlimb grip strength being affected in SOD1-G93A mice from the onset of testing (64 days of age). Rotarod performance was affected by 71 days of age. Locomotor activity was not affected, even near end-stage. Bulbar involvement appeared much later, with tongue motility being affected by 100 days of age. Tongue force was affected by 115 days of age. To our knowledge, these findings are the first to describe the onset of bulbar v. spinal motor signs and characterize orolingual motor deficits in this preclinical model of ALS.

Background: Skeletal muscles play an important role in systemic glucose homeostasis and are purported to be the origin of the altered metabolic state observed in amyotrophic lateral sclerosis (ALS). Objective: The purpose of this study was to evaluate whole-body and muscle-specific glucose metabolism in the SOD1-G93A mouse model of ALS. Methods: We assessed glucose tolerance in early-, middle-, and late-stage SOD1-G93A and control mice using an intraperitoneal glucose tolerance test. We then measured the respiratory exchange ratio (CO₂ production/O₂ consumption) as a function of fasting and feeding using indirect calorimetry in a subset of male mice at these time points. Finally, muscles from all mice were harvested to evaluate basal and insulin-stimulated glucose transport in fast- and slow-twitch muscles. Results: No changes in systemic glucose clearance were observed in SOD1-G93A mice at any stage, nor were there changes in fasting insulin levels. Indirect calorimetry revealed an increase in the respiratory exchange ratio during the fed state at middle, but not at early or late stages of disease. Middle-stage SOD1-G93A mice exhibited decreased insulin-stimulated glucose uptake in fast-twitch, but not slow-twitch, skeletal muscle. Late-stage SOD1-G93A mice exhibited decreased insulin-stimulated glucose uptake in both fast- and slow-twitch muscle, as well as increased basal (non-insulin-stimulated) glucose uptake. Conclusions: These results suggest that alterations in muscle metabolism occur in a fiber-type-specific manner in ALS, but do not necessarily lead to whole-body metabolic changes in SOD1-G93A mice.

Much of our understanding of the effects of diabetes on the peripheral nervous system is derived from models induced by streptozotocin in which hyperglycemia is rapidly caused by pancreatic beta-cell destruction. Here, we have quantified sensory impairments over time in leptin receptor (lepr)-null mutant -/- mice, a type 2 model of diabetes in which the absence of leptin receptor signaling leads to obesity and chronic hyperglycemia by 4 weeks of age. To assess these mice as a model for peripheral neuropathy, we quantified the responsiveness of lepr -/- mice to mechanical, thermal, and chemogenic stimuli, as well as epidermal and dermal innervation of the hind paw. Compared with wild-type +/+ and heterozygous +/- mice, lepr -/- mice displayed reduced sensitivity to mechanical stimuli by 6 weeks of age, and however, responses to noxious heat were normal. Lepr -/- mice also devoted less activity to their injected paw during the second phase following formalin administration. However, epidermal and dermal innervation of lepr -/- mice was not different from that of lepr +/+ and +/- mice even after 10 weeks of hyperglycemia, suggesting that cutaneous innervation is resistant to chronic hyperglycemia in these mice. These results suggest that certain rodent nocifensive behaviors may be linked to the abundance of cutaneous innervation, while others are not. Finally, these results reveal that the lepr -/- mice may not be useful to study neuropathy associated with distal axonal degeneration but may be better suited for studies of hyperglycemia-induced sensory neuron dysfunction without distal nerve loss.

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Normal aging is associated with both locomotor and orolingual motor deficits. Preclinical studies of motor function in normal aging, however, have focused primarily on locomotor activity. The purpose of this study was to measure age-related changes in orolingual motor function and compare these changes between two rat strains commonly used in aging studies: Fischer 344 (F344) and Fischer 344/Brown Norway hybrid (F344/BN) rats. Rats (6-, 12-, 18-and 24-months of age) were trained to lick water from an isometric force-sensing operandum so that the number of licks per session, licking rhythm (licks/second) and lick force could be measured. In both strains, the number of licks per session was greatest in the oldest group, while this measure was greater for F344/BN rats at all ages. Peak tongue force increased with age in F344/BN rats, did not change with age in the F344 rats, and was greater for the F344/BN rats at all ages. Both strains exhibited an age-related slowing of licking rhythm beginning with the 18-month-old group. These findings suggest that despite lifespan differences between these two rat strains, diminished tongue motility emerges at the same age.

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