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      Striking Denervation of Neuromuscular Junctions without Lumbar Motoneuron Loss in Geriatric Mouse Muscle

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          Abstract

          Reasons for the progressive age-related loss of skeletal muscle mass and function, namely sarcopenia, are complex. Few studies describe sarcopenia in mice, although this species is the mammalian model of choice for genetic intervention and development of pharmaceutical interventions for muscle degeneration. One factor, important to sarcopenia-associated neuromuscular change, is myofibre denervation. Here we describe the morphology of the neuromuscular compartment in young (3 month) compared to geriatric (29 month) old female C57Bl/6J mice. There was no significant difference in the size or number of motoneuron cell bodies at the lumbar level (L1–L5) of the spinal cord at 3 and 29 months. However, in geriatric mice, there was a striking increase (by ∼2.5 fold) in the percentage of fully denervated neuromuscular junctions (NMJs) and associated deterioration of Schwann cells in fast extensor digitorum longus (EDL), but not in slow soleus muscles. There were also distinct changes in myofibre composition of lower limb muscles (tibialis anterior (TA) and soleus) with a shift at 29 months to a faster phenotype in fast TA muscle and to a slower phenotype in slow soleus muscle. Overall, we demonstrate complex changes at the NMJ and muscle levels in geriatric mice that occur despite the maintenance of motoneuron cell bodies in the spinal cord. The challenge is to identify which components of the neuromuscular system are primarily responsible for the marked changes within the NMJ and muscle, in order to selectively target future interventions to reduce sarcopenia.

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          Most cited references60

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          Unbiased stereological estimation of the total number of neurons in thesubdivisions of the rat hippocampus using the optical fractionator.

          A stereological method for obtaining estimates of the total number of neurons in five major subdivisions of the rat hippocampus is described. The new method, the optical fractionator, combines two recent developments in stereology: a three-dimensional probe for counting neuronal nuclei, the optical disector, and a systematic uniform sampling scheme, the fractionator. The optical disector results in unbiased estimates of neuron number, i.e., estimates that are free of assumptions about neuron size and shape, are unaffected by lost caps and overprojection, and approach the true number of neurons in an unlimited manner as the number of samples is increased. The fractionator involves sampling a known fraction of a structural component. In the case of neuron number, a zero dimensional quantity, it provides estimates that are unaffected by shrinkage before, during, and after processing of the tissue. Because the fractionator involves systematic sampling, it also results in highly efficient estimates. Typically only 100-200 neurons must be counted in an animal to obtain a precision that is compatible with experimental studies. The methodology is compared with those used in earlier works involving estimates of neuron number in the rat hippocampus and a number of new stereological methods that have particular relevance to the quantitative study of the structure of the nervous system are briefly described in an appendix.
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            Epidemiology of sarcopenia among the elderly in New Mexico.

            Muscle mass decreases with age, leading to "sarcopenia," or low relative muscle mass, in elderly people. Sarcopenia is believed to be associated with metabolic, physiologic, and functional impairments and disability. Methods of estimating the prevalence of sarcopenia and its associated risks in elderly populations are lacking. Data from a population-based survey of 883 elderly Hispanic and non-Hispanic white men and women living in New Mexico (the New Mexico Elder Health Survey, 1993-1995) were analyzed to develop a method for estimating the prevalence of sarcopenia. An anthropometric equation for predicting appendicular skeletal muscle mass was developed from a random subsample (n = 199) of participants and was extended to the total sample. Sarcopenia was defined as appendicular skeletal muscle mass (kg)/height2 (m2) being less than two standard deviations below the mean of a young reference group. Prevalences increased from 13-24% in persons under 70 years of age to >50% in persons over 80 years of age, and were slightly greater in Hispanics than in non-Hispanic whites. Sarcopenia was significantly associated with self-reported physical disability in both men and women, independent of ethnicity, age, morbidity, obesity, income, and health behaviors. This study provides some of the first estimates of the extent of the public health problem posed by sarcopenia.
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              Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise.

              The cellular basis of age-related behavioral decline remains obscure but alterations in synapses are likely candidates. Accordingly, the beneficial effects on neural function of caloric restriction and exercise, which are among the most effective anti-aging treatments known, might also be mediated by synapses. As a starting point in testing these ideas, we studied the skeletal neuromuscular junction (NMJ), a large, accessible peripheral synapse. Comparison of NMJs in young adult and aged mice revealed a variety of age-related structural alterations, including axonal swellings, sprouting, synaptic detachment, partial or complete withdrawal of axons from some postsynaptic sites, and fragmentation of the postsynaptic specialization. Alterations were significant by 18 mo of age and severe by 24 mo. A life-long calorie-restricted diet significantly decreased the incidence of pre- and postsynaptic abnormalities in 24-mo-old mice and attenuated age-related loss of motor neurons and turnover of muscle fibers. One month of exercise (wheel running) in 22-mo-old mice also reduced age-related synaptic changes but had no effect on motor neuron number or muscle fiber turnover. Time-lapse imaging in vivo revealed that exercise partially reversed synaptic alterations that had already occurred. These results demonstrate a critical effect of aging on synaptic structure and provide evidence that interventions capable of extending health span and lifespan can partially reverse these age-related synaptic changes.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                2 December 2011
                : 6
                : 12
                : e28090
                Affiliations
                [1 ]School of Anatomy and Human Biology, The University of Western Australia, Perth, Western Australia, Australia
                [2 ]Queensland Brain Institute, The University of Queensland, St. Lucia, Queensland, Australia
                [3 ]School of Animal Biology, The University of Western Australia, Perth, Western Australia, Australia
                University of Houston, United States of America
                Author notes

                Conceived and designed the experiments: RJC SD MG TS. Performed the experiments: RJC JV SD TS. Analyzed the data: RJC JV SD TS. Wrote the paper: RJC SD MG TS.

                Article
                PONE-D-11-11057
                10.1371/journal.pone.0028090
                3229526
                22164231
                efa9bade-a7cc-4b0d-bc91-928b7419bb01
                Chai et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 21 June 2011
                : 1 November 2011
                Page count
                Pages: 11
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Musculoskeletal System
                Muscle
                Muscle Types
                Neurological System
                Motor Systems
                Molecular Cell Biology
                Cellular Types
                Muscle Fibers
                Muscle Cells
                Neuroscience
                Neurophysiology
                Neuromuscular Junction
                Medicine
                Geriatrics
                Neurology
                Motor Neuron Diseases

                Uncategorized
                Uncategorized

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