Cheung, Sang Won

Abstract Striated muscle weakness and motor neuron (MN) death are associated with aging. These alterations affect both brainstem and spinal motor pools, including hypoglossal MNs innervating the tongue and lumbar MNs innervating the lower/hindlimbs. Both MNs and striated muscles exhibit type‐selective motor unit vulnerability, where larger MNs (likely fast fatigable motor units) and type IIx/b muscles are vulnerable to death and atrophy, respectively. These findings have been cemented in humans to some degree and in Fischer 344 and Wistar rats. However, MN survival in old age has not been evaluated in Sprague–Dawley rats. Here, in 6‐ (young) and 24‐month‐old (old) female and male Sprague–Dawley rats, we performed stereological MN counts on hypoglossal and lumbar MNs using 16 μm Nissl‐stained sections. We observed a 35% loss of hypoglossal and lumbar MNs in old age. Although mean MN somal surface areas were moderately reduced in hypoglossal and unchanged in lumbar MNs with age, frequency histogram analyses revealed a disproportionate loss of larger MN in old age hypoglossal and lumbar pools. These findings reveal reliable and robust observations of MN death in rats. This neurogenic aspect of neuromotor impairment with age may be a key driver of sarcopenia and frailty in the elderly.

Abstract Age‐associated muscle weakness and atrophy of limb muscles, termed sarcopenia, is a major factor in the morbidity of the elderly. It is becoming increasingly recognized that a substantial contribution to the sarcopenic phenotype arises from motor neuron (MN) death in old age and subsequent muscle denervation. In human and rodent models, mitochondrial dysfunction is a leading culprit in both muscle and MN deterioration with age. In other motor pools within the Fischer 344 (F344) aging rat model, we showed that sarcopenia is selective to type IIx/b muscle fibers. We also showed a loss of larger MNs and denervation of the IIx/b fibers, which together comprise more fatigable fast (type FF) motor units. This selective vulnerability of larger MNs and type IIx/b muscle fibers to sarcopenia is further reflected by reductions in oxidative capacity of IIx/b fibers, as assayed by determining the maximum velocity of the succinate dehydrogenase reaction (SDHmax). Here, we hypothesize similar changes will occur in F344 tibialis anterior (TA) muscle from young (6‐months) and old (24‐months) groups. We also predict lumbar MN death in young and old F344 rats. We found selective atrophy of type IIx/b fibers in the TA from old rats. In old age, SDHmax was reduced but only in IIx/b TA fibers. These muscle observations were concomitant with the death of larger lumbar MNs in old age. This study indicates the remarkable selectivity of type FF TA motor units to age‐associated perturbations and sarcopenia.

Neuroplastic changes in phrenic motor neurons that underlie recovery from spinal cord injury may be mediated by perineuronal nets. We show that changes in perineuronal nets around phrenic motor neurons occur within 7 days after cervical spinal cord injury, and that the increase in perineuronal nets around larger phrenic motor neurons was more pronounced. These changes are consistent with substantial reorganization of the neural network onto intact phrenic motor neurons following cervical spinal cord injury.

Abstract Age‐related neuromuscular dysfunction is widely recognized; however, the extent to which aging is accompanied by motor neuron (MN) loss remains underexplored. This review evaluates evidence for MN loss with aging across species and anatomical motor pools. We synthesize PUBMED studies in humans, non‐human primates, rats and mice within the spinal cord and brainstem. Attention was given to the methodological approach used to quantify MNs and categorized based on what MNs were quantified (specific pools, vertebral levels, lateral motor columns). Methods were assessed qualitatively, based on stereological and non‐stereological density counting approaches, and the staining techniques identified as optimal or suboptimal by defined criteria. To facilitate cross‐study comparison we conducted quantitative assessments including: coefficients of variance, percentage differences between groups and standardized effect sizes calculated with Cohen's d . Across species and anatomical regions, the overall literature supports the presence of age‐related MN loss. Evidence is strongest in studies using robust counting approaches such as stereology, and appropriate MN markers. As age‐related MN degeneration is more heavily investigated and becomes a locus of intervention, future work must employ rigorous methodological standards to accurately determine the extent, regional specificity, and functional consequence of aging MN loss.