The Neuromuscular Junction: Aging at the Crossroad between Nerves and Muscle

Marta Gonzalez-Freire, Rafael de Cabo, Stephanie A Studenski, Luigi Ferrucci, Marta Gonzalez-Freire, Rafael de Cabo, Stephanie A Studenski, Luigi Ferrucci

Abstract

Aging is associated with a progressive loss of muscle mass and strength and a decline in neurophysiological functions. Age-related neuromuscular junction (NMJ) plays a key role in musculoskeletal impairment that occurs with aging. However, whether changes in the NMJ precede or follow the decline of muscle mass and strength remains unresolved. Many factors such as mitochondrial dysfunction, oxidative stress, inflammation, changes in the innervation of muscle fibers, and mechanical properties of the motor units probably perform an important role in NMJ degeneration and muscle mass and strength decline in late life. This review addresses the primary events that might lead to NMJ dysfunction with aging, including studies on biomarkers, signaling pathways, and animal models. Interventions such as caloric restriction and exercise may positively affect the NMJ through this mechanism and attenuate the age-related progressive impairment in motor function.

Keywords: aging; denervation; motor unit; neuromuscular junction; sarcopenia.

Figures

Figure 1
Figure 1
The architecture of a neuromuscular junction (NMJ). (A, B) The NMJ is composed of three elements: pre-synaptic (motor nerve terminal), intrasynaptic (synaptic basal lamina), and post-synaptic component (muscle fiber and muscle membrane) (Punga and Ruegg, 2012). When the action potential reaches the motor nerve terminal the calcium channels open and the calcium enters in the neuron and delivers ACh in the synaptic cleft. (C) AChR activates the DHPRs located in the sarcolemma and by induction the RyRs. Calcium released from the sarcoplasmic reticulum through the RyRs binds to troponin C and allows cross-bridge cycling and force production.
Figure 2
Figure 2
Primary causes of NMJ dysfunction during aging. Factors such as mitochondrial dysfunction, oxidative stress, inflammation, and changes in the innervation of muscle fiber and mechanical properties of the motor units could play an important role in the NMJ degeneration and development of sarcopenia.
Figure 3
Figure 3
Changes in the neuromuscular junction with aging. Structural changes together with functional alterations result in a NMJ impairment during aging. The excitation–contraction uncoupling leads to a loss of communication between the nervous and muscular system, causing a decline in skeletal muscle strength and muscle mass.

References

    1. Afilalo J., Alexander K. P., Mack M. J., Maurer M. S., Green P., Allen L. A., et al. (2014). Frailty assessment in the cardiovascular care of older adults. J. Am. Coll. Cardiol. 63, 747–76210.1016/j.jacc.2013.09.070
    1. Andersen J. L. (2003). Muscle fibre type adaptation in the elderly human muscle. Scand. J. Med. Sci. Sports 13, 40–4710.1034/j.1600-0838.2003.00299.x
    1. Anderson R. M., Weindruch R. (2012). The caloric restriction paradigm: implications for healthy human aging. Am. J. Hum. Biol. 24, 101–10610.1002/ajhb.22243
    1. Apel P. J., Ma J., Callahan M., Northam C. N., Alton T. B., Sonntag W. E., et al. (2010). Effect of locally delivered IGF-1 on nerve regeneration during aging: an experimental study in rats. Muscle Nerve 41, 335–34110.1002/mus.21485
    1. Arnold A. S., Gill J., Christe M., Ruiz R., McGuirk S., St-Pierre J., et al. (2014). Morphological and functional remodelling of the neuromuscular junction by skeletal muscle PGC-1alpha. Nat Commun 5, 3569.10.1038/ncomms4569
    1. Arrowsmith J. E. (2007). The neuromuscular junction. Surgery (Oxford) 25, 105–11110.1016/j.mpsur.2007.02.001
    1. Baines H. L., Turnbull D. M., Greaves L. C. (2014). Human stem cell aging: do mitochondrial DNA mutations have a causal role? Aging Cell 13, 201–20510.1111/acel.12199
    1. Banker B. Q., Kelly S. S., Robbins N. (1983). Neuromuscular transmission and correlative morphology in young and old mice. J. Physiol. 339, 355–377
    1. Barrett E. F., Barrett J. N., David G. (2011). Mitochondria in motor nerve terminals: function in health and in mutant superoxide dismutase 1 mouse models of familial ALS. J. Bioenerg. Biomembr. 43, 581–58610.1007/s10863-011-9392-1
    1. Belluardo N., Westerblad H., Mudo G., Casabona A., Bruton J., Caniglia G., et al. (2001). Neuromuscular junction disassembly and muscle fatigue in mice lacking neurotrophin 4. Mol. Cell. Neurosci. 18, 56–6710.1006/mcne.2001.1001
    1. Bodine S. C., Latres E., Baumhueter S., Lai V. K., Nunez L., Clarke B. A., et al. (2001). Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294, 1704–170810.1126/science.1065874
    1. Bolliger M. F., Zurlinden A., Luscher D., Butikofer L., Shakhova O., Francolini M., et al. (2010). Specific proteolytic cleavage of agrin regulates maturation of the neuromuscular junction. J. Cell Sci. 123(Pt 22), 3944–395510.1242/jcs.072090
    1. Butikofer L., Zurlinden A., Bolliger M. F., Kunz B., Sonderegger P. (2011). Destabilization of the neuromuscular junction by proteolytic cleavage of agrin results in precocious sarcopenia. FASEB J. 25, 4378–439310.1096/fj.11-191262
    1. Chai R. J., Vukovic J., Dunlop S., Grounds M. D., Shavlakadze T. (2011). Striking denervation of neuromuscular junctions without lumbar motoneuron loss in geriatric mouse muscle. PLoS ONE 6:e28090.10.1371/journal.pone.0028090
    1. Cheng A., Morsch M., Murata Y., Ghazanfari N., Reddel S. W., Phillips W. D. (2013). Sequence of age-associated changes to the mouse neuromuscular junction and the protective effects of voluntary exercise. PLoS ONE 8:e67970.10.1371/journal.pone.0067970
    1. Chistiakov D. A., Sobenin I. A., Revin V. V., Orekhov A. N., Bobryshev Y. V. (2014). Mitochondrial Aging and Age-Related Dysfunction of Mitochondria. BioMed. Res. Int. 2014, 238463.10.1155/2014/238463
    1. Clark D. J., Fielding R. A. (2012). Neuromuscular contributions to age-related weakness. J Gerontol A. Biol. Sci. Med. Sci. 67, 41–4710.1093/gerona/glr041
    1. Clark D. J., Pojednic R. M., Reid K. F., Patten C., Pasha E. P., Phillips E. M., et al. (2013). Longitudinal decline of neuromuscular activation and power in healthy older adults. J. Gerontol. 68, 1419–142510.1093/gerona/glt036
    1. Conboy I. M., Rando T. A. (2012). Heterochronic parabiosis for the study of the effects of aging on stem cells and their niches. Cell Cycle (Georgetown, Tex.) 11, 2260–226710.4161/cc.20437
    1. Degens H. (2010). The role of systemic inflammation in age-related muscle weakness and wasting. Scand. J. Med. Sci. Sports 20, 28–3810.1111/j.1600-0838.2009.01018.x
    1. Degens H., Alway S. E. (2006). Control of muscle size during disuse, disease, and aging. Int. J. Sports Med. 27, 94–9910.1055/s-2005-837571
    1. Delbono O. (2000). Regulation of excitation contraction coupling by insulin-like growth factor-1 in aging skeletal muscle. J. Nutr. Health Aging 4, 162–164
    1. Delbono O. (2003). Neural control of aging skeletal muscle. Aging Cell 2, 21–2910.1046/j.1474-9728.2003.00011.x
    1. Delbono O., O’Rourke K. S., Ettinger W. H. (1995). Excitation-calcium release uncoupling in aged single human skeletal muscle fibers. J. Memb. Biol. 148, 211–22210.1007/BF00235039
    1. Delbono O., Renganathan M., Messi M. L. (1997). Excitation-Ca2+ release-contraction coupling in single aged human skeletal muscle fiber. Muscle Nerve Suppl. 5, S88–S9210.1002/(SICI)1097-4598(1997)5+<88::AID-MUS21>;2-U
    1. Derbre F., Gomez-Cabrera M. C., Nascimento A. L., Sanchis-Gomar F., Martinez-Bello V. E., Tresguerres J. A., et al. (2012). Age associated low mitochondrial biogenesis may be explained by lack of response of PGC-1alpha to exercise training. Age (Dordr) 34, 669–67910.1007/s11357-011-9264-y
    1. Deschenes M. R. (2011). Motor unit and neuromuscular junction remodeling with aging. Curr Aging Sci 4, 209–22010.2174/1874609811104030209
    1. Deschenes M. R., Roby M. A., Eason M. K., Harris M. B. (2010). Remodeling of the neuromuscular junction precedes sarcopenia related alterations in myofibers. Exp. Gerontol. 45, 389–39310.1016/j.exger.2010.03.007
    1. Drey M., Sieber C. C., Bauer J. M., Uter W., Dahinden P., Fariello R. G., et al. (2013). C-terminal agrin fragment as a potential marker for sarcopenia caused by degeneration of the neuromuscular junction. Exp. Gerontol. 48, 76–8010.1016/j.exger.2012.05.021
    1. Dupuis L., Gonzalez de Aguilar J.-L., Echaniz-Laguna A., Eschbach J., Rene F., Oudart H., et al. (2009). Muscle mitochondrial uncoupling dismantles neuromuscular junction and triggers distal degeneration of motor neurons. PLoS ONE 4:e5390.10.1371/journal.pone.0005390
    1. Dupuis L., Oudart H., Rene F., Gonzalez de Aguilar J. L., Loeffler J. P. (2004). Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. Proc. Natl. Acad. Sci. U S A. 101, 11159–1116410.1073/pnas.0402026101
    1. Dupuis L., Pradat P. F., Ludolph A. C., Loeffler J. P. (2011). Energy metabolism in amyotrophic lateral sclerosis. Lancet Neurol. 10, 75–8210.1016/S1474-4422(10)70224-6
    1. Fahim M. A. (1997). Endurance exercise modulates neuromuscular junction of C57BL/6NNia aging mice. J. Appl. Physiol. 83, 59–66
    1. Ferrucci L., Baroni M., Ranchelli A., Lauretani F., Maggio M., Mecocci P., et al. (2014). Interaction between bone and muscle in older persons with mobility limitations. Curr. Pharm. Des. 20, 3178–319710.2174/13816128113196660690
    1. Ferrucci L., Corsi A., Lauretani F., Bandinelli S., Bartali B., Taub D. D., et al. (2005). The origins of age-related proinflammatory state. Blood 105, 2294–229910.1182/blood-2004-07-2599
    1. Ferrucci L., de Cabo R., Knuth N. D., Studenski S. (2012). Of Greek heroes, wiggling worms, mighty mice, and old body builders. J Gerontol. A. Biol. Sci. Med. Sci. 67, 13–1610.1093/gerona/glr046
    1. Ferrucci L., Giallauria F., Schlessinger D. (2008). Mapping the road to resilience: novel math for the study of frailty. Mech. Ageing Dev. 129, 677–67910.1016/j.mad.2008.09.007
    1. Ferrucci L., Harris T. B., Guralnik J. M., Tracy R. P., Corti M. C., Cohen H. J., et al. (1999). Serum IL-6 level and the development of disability in older persons. J. Am. Geriatr. Soc. 47, 639–646
    1. Fontana L., Partridge L., Longo V. D. (2010). Extending healthy life span – from yeast to humans. Science 328, 321–32610.1126/science.1172539
    1. Franceschi C., Capri M., Monti D., Giunta S., Olivieri F., Sevini F., et al. (2007). Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 128, 92–10510.1016/j.mad.2006.11.016
    1. Franke B., Gasch A., Rodriguez D., Chami M., Khan M. M., Rudolf R., et al. (2014). Molecular basis for the fold organization and sarcomeric targeting of the muscle atrogin MuRF1. Open Biol. 4, 130172.10.1098/rsob.130172
    1. Furlow J. D., Watson M. L., Waddell D. S., Neff E. S., Baehr L. M., Ross A. P., et al. (2013). Altered gene expression patterns in muscle ring finger 1 null mice during denervation- and dexamethasone-induced muscle atrophy. Physiol. Genomics 45, 1168–118510.1152/physiolgenomics.00022.2013
    1. Garcia M. L., Fernandez A., Solas M. T. (2013). Mitochondria, motor neurons and aging. J. Neurol. Sci. 330, 18–2610.1016/j.jns.2013.03.019
    1. Garcia-Valles R., Gomez-Cabrera M. C., Rodriguez-Manas L., Garcia-Garcia F. J., Diaz A., Noguera I., et al. (2013). Life-long spontaneous exercise does not prolong lifespan but improves health span in mice. Longev. Healthspan 2, 14.10.1186/2046-2395-2-14
    1. Gillette-Guyonnet S., Vellas B. (2008). Caloric restriction and brain function. Curr. Opin. Clin. Nutr. Metab. Care 11, 686–69210.1097/MCO.0b013e328313968f
    1. Glass D., Roubenoff R. (2010). Recent advances in the biology and therapy of muscle wasting. Ann. N Y Acad. Sci. 1211, 25–3610.1111/j.1749-6632.2010.05809.x
    1. Gomez-Pinilla F. (2011). The combined effects of exercise and foods in preventing neurological and cognitive disorders. Prev. Med. 52(Suppl. 1), S75–S8010.1016/j.ypmed.2011.01.023
    1. Gomez-Pinilla F., Ying Z., Roy R. R., Molteni R., Edgerton V. R. (2002). Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity. J. Neurophysiol. 88, 2187–219510.1152/jn.00152.2002
    1. Gordon T., Udina E., Verge V. M. K., de Chaves E. I. P. (2009). Brief electrical stimulation accelerates axon regeneration in the peripheral nervous system and promotes sensory axon regeneration in the central nervous system. Motor Control 13, 412–441
    1. Gouspillou G., Hepple R. T. (2013). Facts and controversies in our understanding of how caloric restriction impacts the mitochondrion. Exp. Gerontol. 48, 1075–108410.1016/j.exger.2013.03.004
    1. Gouspillou G., Picard M., Godin R., Burelle Y., Hepple R. T. (2013). Role of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) in denervation-induced atrophy in aged muscle: facts and hypotheses. Longev. Healthspan 2, 13.10.1186/2046-2395-2-13
    1. Gyorkos A. M., McCullough M. J., Spitsbergen J. M. (2014). Glial cell line-derived neurotrophic factor (GDNF) expression and NMJ plasticity in skeletal muscle following endurance exercise. Neuroscience 257, 111–11810.1016/j.neuroscience.2013.10.068
    1. Handschin C., Kobayashi Y. M., Chin S., Seale P., Campbell K. P., Spiegelman B. M. (2007). PGC-1alpha regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy. Genes Dev. 21, 770–78310.1101/gad.1525107
    1. Hettwer S., Dahinden P., Kucsera S., Farina C., Ahmed S., Fariello R., et al. (2013). Elevated levels of a C-terminal agrin fragment identifies a new subset of sarcopenia patients. Exp. Gerontol. 48, 69–7510.1016/j.exger.2012.03.002
    1. Huang E. J., Reichardt L. F. (2001). Neurotrophins: roles in neuronal development and function. Ann. Rev. Neurosci. 24, 677–73610.1146/annurev.neuro.24.1.677
    1. Hurley B. F., Hanson E. D., Sheaff A. K. (2011). Strength training as a countermeasure to aging muscle and chronic disease. Sports Med. 41, 289–30610.2165/11585920-000000000-00000
    1. Ibebunjo C., Chick J. M., Kendall T., Eash J. K., Li C., Zhang Y., et al. (2013). Genomic and proteomic profiling reveals reduced mitochondrial function and disruption of the neuromuscular junction driving rat sarcopenia. Mol. Cel. Biol. 33, 194–21210.1128/MCB.01036-12
    1. Jang Y. C., Liu Y., Hayworth C. R., Bhattacharya A., Lustgarten M. S., Muller F. L., et al. (2012). Dietary restriction attenuates age-associated muscle atrophy by lowering oxidative stress in mice even in complete absence of CuZnSOD. Aging Cell 11, 770–78210.1111/j.1474-9726.2012.00843.x
    1. Jang Y. C., Van Remmen H. (2009). The mitochondrial theory of aging: insight from transgenic and knockout mouse models. Exp. Gerontol. 44, 256–26010.1016/j.exger.2008.12.006
    1. Jang Y. C., Van Remmen H. (2011). Age-associated alterations of the neuromuscular junction. Exp. Gerontol. 46, 193–19810.1016/j.exger.2010.08.029
    1. Jiang X., Tian F., Du Y., Copeland N. G., Jenkins N. A., Tessarollo L., et al. (2008). BHLHB2 controls Bdnf promoter 4 activity and neuronal excitability. J. Neurosci. 28, 1118–113010.1523/JNEUROSCI.2262-07.2008
    1. Kallen R. G., Sheng Z. H., Yang J., Chen L. Q., Rogart R. B., Barchi R. L. (1990). Primary structure and expression of a sodium channel characteristic of denervated and immature rat skeletal muscle. Neuron 4, 233–24210.1016/0896-6273(90)90098-Z
    1. Kawabuchi M., Tan H., Wang S. (2011). Age affects reciprocal cellular interactions in neuromuscular synapses following peripheral nerve injury. Ageing Res. Rev. 10, 43–5310.1016/j.arr.2010.10.003
    1. Kawabuchi M., Zhou C. J., Wang S., Nakamura K., Liu W. T., Hirata K. (2001). The spatio temporal relationship among Schwann cells, axons and post-synaptic acetylcholine receptor regions during muscle reinnervation in aged rats. Anat. Rec. 264, 183–20210.1002/ar.1159
    1. Khan M. M., Strack S., Wild F., Hanashima A., Gasch A., Brohm K., et al. (2014). Role of autophagy, SQSTM1, SH3GLB1, and TRIM63 in the turnover of nicotinic acetylcholine receptors. Autophagy 10, 123–13610.4161/auto.26841
    1. Kim H. A., Mindos T., Parkinson D. B. (2013). Plastic fantastic: Schwann cells and repair of the peripheral nervous system. Stem Cells Transl. Med. 2, 553–55710.5966/sctm.2013-0011
    1. Korkut C., Budnik V. (2009). WNTs tune up the neuromuscular junction. Nat. Rev. Neurosci. 10, 627–63410.1038/nrn2681
    1. Kraner S. D., Novak K. R., Wang Q., Peng J., Rich M. M. (2012). Altered sodium channel-protein associations in critical illness myopathy. Skelet. Muscle 2, 17.10.1186/2044-5040-2-17
    1. Kurokawa K., Mimori Y., Tanaka E., Kohriyama T., Nakamura S. (1999). Age-related change in peripheral nerve conduction: compound muscle action potential duration and dispersion. Gerontology 45, 168–17310.1159/000022081
    1. Lecker S. H., Jagoe R. T., Gilbert A., Gomes M., Baracos V., Bailey J., et al. (2004). Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression. FASEB J. 18, 39–51
    1. Lexell J. (1995). Human aging, muscle mass, and fiber type composition. J Gerontol. A. Biol. Sci. Med. Sci. 50 Spec No, 11–16
    1. Lexell J. (1997). Evidence for nervous system degeneration with advancing age. J. Nutr. 127, 1011S–1013S
    1. Li H., Kumar Sharma L., Li Y., Hu P., Idowu A., Liu D., et al. (2013). Comparative bioenergetic study of neuronal and muscle mitochondria during aging. Free Rad. Biol. Med. 63, 30–4010.1016/j.freeradbiomed.2013.04.030
    1. Li L., Wu W., Lin L. F., Lei M., Oppenheim R. W., Houenou L. J. (1995). Rescue of adult mouse motoneurons from injury-induced cell death by glial cell line-derived neurotrophic factor. Proc. Natl. Acad. Sci.U S A 92, 9771–977510.1073/pnas.92.21.9771
    1. Li Y., Lee Y. I., Thompson W. J. (2011). Changes in aging mouse neuromuscular junctions are explained by degeneration and regeneration of muscle fiber segments at the synapse. J. Neurosci. 31, 14910–1491910.1523/JNEUROSCI.3590-11.2011
    1. Liang H., Ward W. F., Jang Y. C., Bhattacharya A., Bokov A. F., Li Y., et al. (2011). PGC-1alpha protects neurons and alters disease progression in an amyotrophic lateral sclerosis mouse model. Muscle Nerve 44, 947–95610.1002/mus.22217
    1. Lie D. C., Weis J. (1998). GDNF expression is increased in denervated human skeletal muscle. Neurosci. Lett. 250, 87–9010.1016/S0304-3940(98)00434-0
    1. Lin L. F., Doherty D. H., Lile J. D., Bektesh S., Collins F. (1993). GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260, 1130–113210.1126/science.8493557
    1. Lin M. T., Beal M. F. (2006). Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787–79510.1038/nature05292
    1. Lipsky R. H., Marini A. M. (2007). Brain-derived neurotrophic factor in neuronal survival and behavior-related plasticity. Ann. NY Acad. Sci 1122, 130–14310.1196/annals.1403.009
    1. Luff A. R. (1998). Age-associated changes in the innervation of muscle fibers and changes in the mechanical properties of motor units. Ann. N. Y. Acad. Sci. 854, 92–10110.1111/j.1749-6632.1998.tb09895.x
    1. Maggio M., Ble A., Ceda G. P., Metter E. J. (2006). Decline in insulin-like growth factor-I levels across adult life span in two large population studies. J. Gerontol. A Biol. Sci. Med. Sci. 61, 182–18310.1093/gerona/61.2.182
    1. Maggio M., De Vita F., Lauretani F., Butto V., Bondi G., Cattabiani C., et al. (2013). IGF-1, the cross road of the nutritional, inflammatory and hormonal pathways to frailty. Nutrients 5, 4184–420510.3390/nu5104184
    1. Manini T. M., Hong S. L., Clark B. C. (2013). Aging and muscle: a neuron’s perspective. Curr. Opin. Clin. Nutr. Metab. Care 16, 21–2610.1097/MCO.0b013e32835b5880
    1. Mayhew M., Renganathan M., Delbono O. (1998). Effectiveness of caloric restriction in preventing age-related changes in rat skeletal muscle. Biochem. Biophys. Res. Commun. 251, 95–9910.1006/bbrc.1998.9438
    1. McCay C. M., Crowell M. F., Maynard L. A. (1935). The effect of retarded growth upon the length of life span and upon the ulti- mate body size. J. Nutr. 10, 63–79
    1. McCullough M. J., Gyorkos A. M., Spitsbergen J. M. (2013). Short-term exercise increases GDNF protein levels in the spinal cord of young and old rats. Neuroscience 240, 258–26810.1016/j.neuroscience.2013.02.063
    1. McCullough M. J., Peplinski N. G., Kinnell K. R., Spitsbergen J. M. (2011). Glial cell line-derived neurotrophic factor protein content in rat skeletal muscle is altered by increased physical activity in vivo and in vitro. Neuroscience 174, 234–24410.1016/j.neuroscience.2010.11.016
    1. McKiernan S. H., Bua E., McGorray J., Aiken J. (2004). Early-onset calorie restriction conserves fiber number in aging rat skeletal muscle. FASEB J. 18, 580–581
    1. Mercken E. M., Carboneau B. A., Krzysik-Walker S. M., de Cabo R. (2012). Of mice and men: the benefits of caloric restriction, exercise, and mimetics. Ageing Res. Rev. 11, 390–39810.1016/j.arr.2011.11.005
    1. Messi M. L., Delbono O. (2003). Target-derived trophic effect on skeletal muscle innervation in senescent mice. J. Neurosci. 23, 1351–1359
    1. Morel J., Rannou F., Talarmin H., Giroux-Metges M. A., Pennec J. P., Dorange G., et al. (2010). Sodium channel Na(V)1.5 expression is enhanced in cultured adult rat skeletal muscle fibers. J. Membr. Biol. 235, 109–11910.1007/s00232-010-9262-5
    1. Muller F. L., Song W., Jang Y. C., Liu Y., Sabia M., Richardson A., et al. (2007). Denervation-induced skeletal muscle atrophy is associated with increased mitochondrial ROS production. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R1159–R116810.1152/ajpregu.00767.2006
    1. Mulligan K. A., Cheyette B. N. R. (2012). Wnt signaling in vertebrate neural development and function. J. Neuroimmune Pharmacol. 7, 774–78710.1007/s11481-012-9404-x
    1. Musaro A., McCullagh K., Paul A., Houghton L., Dobrowolny G., Molinaro M., et al. (2001). Localized IGF-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nat. Genet. 27, 195–20010.1038/84839
    1. Navarro A., Boveris A. (2009). Brain mitochondrial dysfunction and oxidative damage in Parkinson’s disease. J. Bioenerg. Biomembr 41, 517–52110.1007/s10863-009-9250-6
    1. Nguyen Q. T., Parsadanian A. S., Snider W. D., Lichtman J. W. (1998). Hyperinnervation of neuromuscular junctions caused by GDNF overexpression in muscle. Science 279, 1725–172910.1126/science.279.5357.1725
    1. Nishimune H., Numata T., Chen J., Aoki Y., Wang Y., Starr M. P., et al. (2012). Active zone protein Bassoon co-localizes with presynaptic calcium channel, modifies channel function, and recovers from aging related loss by exercise. PLoS ONE 7:e38029.10.1371/journal.pone.0038029
    1. Nishimune H., Stanford J. A., Mori Y. (2014). Role of exercise in maintaining the integrity of the neuromuscular junction. Muscle & Nerve 49, 315–32410.1002/mus.24095
    1. Nordquist J., Hoglund A. S., Norman H., Tang X., Dworkin B., Larsson L. (2007). Transcription factors in muscle atrophy caused by blocked neuromuscular transmission and muscle unloading in rats. Mol. Med. 13, 461–47010.2119/2006-00066
    1. Okerlund N. D., Cheyette B. N. (2011). Synaptic Wnt signaling; a contributor to major psychiatric disorders? J. Neurodev. Disord. 3, 162–17410.1007/s11689-011-9083-6
    1. Payne A. M., Zheng Z., Messi M. L., Milligan C. E., Gonzalez E., Delbono O. (2006). Motor neurone targeting of IGF-1 prevents specific force decline in ageing mouse muscle. J. Physiol. 570(Pt 2), 283–29410.1113/jphysiol.2005.100032
    1. Peng H. B., Yang J. F., Dai Z., Lee C. W., Hung H. W., Feng Z. H., et al. (2003). Differential effects of neurotrophins and Schwann cell-derived signals on neuronal survival/growth and synaptogenesis. J. Neurosci. 23, 5050–5060
    1. Peterson C. M., Johannsen D. L., Ravussin E. (2012). Skeletal muscle mitochondria and aging: a review. J. Aging Res. 2012, 194821.10.1155/2012/194821
    1. Punga A. R., Ruegg M. A. (2012). Signaling and aging at the neuromuscular synapse: lessons learnt from neuromuscular diseases. Curr. Opin. Pharmacol. 12, 340–34610.016/j.coph.2012.02.002
    1. Rangaraju S., Hankins D., Madorsky I., Madorsky E., Lee W. H., Carter C. S., et al. (2009). Molecular architecture of myelinated peripheral nerves is supported by calorie restriction with aging. Aging Cell 8, 178–19110.1111/j.1474-9726.2009.00460.x
    1. Rangaraju S., Notterpek L. (2011). Autophagy aids membrane expansion by neuropathic Schwann cells. Autophagy 7, 238–23910.4161/auto.7.2.14278
    1. Rannou F., Pennec J.-P., Morel J., Gueret G., Leschiera R., Droguet M., et al. (2011). Na v1.4 and Na v1.5 are modulated differently during muscle immobilization and contractile phenotype conversion. J. Appl. Physiol. 111, 495–50710.1152/japplphysiol.01136.2010
    1. Reid K. F., Doros G., Clark D. J., Patten C., Carabello R. J., Cloutier G. J., et al. (2012). Muscle power failure in mobility-limited older adults: preserved single fiber function despite lower whole muscle size, quality and rate of neuromuscular activation. Eur J. Appl. Physiol. 112, 2289–230110.1007/s00421-011-2200-0
    1. Reid K. F., Pasha E., Doros G., Clark D. J., Patten C., Phillips E. M., et al. (2014). Longitudinal decline of lower extremity muscle power in healthy and mobility-limited older adults: influence of muscle mass, strength, composition, neuromuscular activation and single fiber contractile properties. Eur. J. Appl. Physiol. 114, 29–3910.1007/s00421-013-2728-2
    1. Rocha M. C., Pousinha P. A., Correia A. M., Sebastiao A. M., Ribeiro J. A. (2013). Early changes of neuromuscular transmission in the SOD1(G93A) mice model of ALS start long before motor symptoms onset. PLoS ONE 8:e73846.10.1371/journal.pone.0073846
    1. Rosenheimer J. L., Smith D. O. (1985). Differential changes in the end-plate architecture of functionally diverse muscles during aging. J. Neurophysiol. 53, 1567–1581
    1. Rosso A. L., Studenski S. A., Chen W. G., Aizenstein H. J., Alexander N. B., Bennett D. A., et al. (2013). Aging, the central nervous system, and mobility. J Gerontol. A. Biol. Sci. Med. Sci. 68, 1379–138610.1093/gerona/glt089
    1. Roubenoff R. (2000). Sarcopenia and its implications for the elderly. Eur. J. Clin. Nutr. 54(Suppl. 3), S40–S4710.1038/sj.ejcn.1601024
    1. Rowan S. L., Rygiel K., Purves-Smith F. M., Solbak N. M., Turnbull D. M., Hepple R. T. (2012). Denervation causes fiber atrophy and myosin heavy chain co-expression in senescent skeletal muscle. PLoS ONE 7:e29082.10.1371/journal.pone.0029082
    1. Rudolf R., Bogomolovas J., Strack S., Choi K. R., Khan M. M., Wagner A., et al. (2013). Regulation of nicotinic acetylcholine receptor turnover by MuRF1 connects muscle activity to endo/lysosomal and atrophy pathways. Age (Dordr) 35, 1663–167410.1007/s11357-012-9468-9
    1. Russ D. W., Lanza I. R. (2011). The impact of old age on skeletal muscle energetics: supply and demand. Curr. Aging Sci. 4, 234–24710.2174/1874609811104030234
    1. Saheb-Al-Zamani M., Yan Y., Farber S. J., Hunter D. A., Newton P., Wood M. D., et al. (2013). Limited regeneration in long acellular nerve allografts is associated with increased Schwann cell senescence. Exp. Neurol. 247, 165–17710.1016/j.expneurol.2013.04.011
    1. Saini A., Faulkner S., Al-Shanti N., Stewart C. (2009). Powerful signals for weak muscles. Ageing Res. Rev. 8, 251–26710.1016/j.arr.2009.02.001
    1. Saini A., Nasser A. S., Stewart C. E. (2007). Waste management – cytokines, growth factors and cachexia. Cytokine Growth Factor Rev. 17, 475–48610.1016/j.cytogfr.2006.09.006
    1. Sakellariou G. K., Davis C. S., Shi Y., Ivannikov M. V., Zhang Y., Vasilaki A., et al. (2014). Neuron-specific expression of CuZnSOD prevents the loss of muscle mass and function that occurs in homozygous CuZnSOD-knockout mice. FASEB J. 28, 1666–168110.1096/fj.13-240390
    1. Sakellariou G. K., Pye D., Vasilaki A., Zibrik L., Palomero J., Kabayo T., et al. (2011). Role of superoxide-nitric oxide interactions in the accelerated age-related loss of muscle mass in mice lacking Cu,Zn superoxide dismutase. Aging Cell 10, 749–76010.1111/j.1474-9726.2011.00709.x
    1. Schaefer A. M., Sanes J. R., Lichtman J. W. (2005). A compensatory subpopulation of motor neurons in a mouse model of amyotrophic lateral sclerosis. J. Comparat. Neurol. 490, 209–21910.1002/cne.20620
    1. Seeburger J. L., Springer J. E. (1993). Experimental rationale for the therapeutic use of neurotrophins in amyotrophic lateral sclerosis. Exp. Neurol. 124, 64–7210.1006/exnr.1993.1176
    1. Shear T. D., Martyn J. A. J. (2009). Physiology and biology of neuromuscular transmission in health and disease. J. Crit. Care 24, 5–1010.1016/j.jcrc.2008.08.002
    1. Smith D. O., Rosenheimer J. L. (1982). Decreased sprouting and degeneration of nerve terminals of active muscles in aged rats. J. Neurophysiol. 48, 100–109
    1. Snow L. M., McLoon L. K., Thompson L. V. (2005). Adult and developmental myosin heavy chain isoforms in soleus muscle of aging Fischer Brown Norway rat. Anat. Rec. A. Discov. Mol. Cell. Evol. Biol. 286, 866–87310.1002/ar.a.20218
    1. Springer J. E., Seeburger J. L., He J., Gabrea A., Blankenhorn E. P., Bergman L. W. (1995). cDNA sequence and differential mRNA regulation of two forms of glial cell line-derived neurotrophic factor in Schwann cells and rat skeletal muscle. Exp. Neurol. 131, 47–5210.1016/0014-4886(95)90006-3
    1. Stamatakou E., Salinas P. C. (2013). Postsynaptic assembly: a role for Wnt signaling. Dev. Neurobiol. 10.1002/dneu.22138
    1. Suetta C., Frandsen U., Jensen L., Jensen M. M., Jespersen J. G., Hvid L. G., et al. (2012). Aging affects the transcriptional regulation of human skeletal muscle disuse atrophy. PLoS ONE 7:e51238.10.1371/journal.pone.0051238
    1. Tevald M. A., Foulis S. A., Lanza I. R., Kent-Braun J. A. (2010). Lower energy cost of skeletal muscle contractions in older humans. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R729–R73910.1152/ajpregu.00713.2009
    1. Valdez G., Tapia J. C., Kang H., Clemenson G. D., Gage F. H., Lichtman J. W., et al. (2010). Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise. Proc. Natl. Acad. Sci. U S A 107, 14863–1486810.1073/pnas.1002220107
    1. Vergani L., Di Giulio A. M., Losa M., Rossoni G., Muller E. E., Gorio A. (1998). Systemic administration of insulin-like growth factor decreases motor neuron cell death and promotes muscle reinnervation. J. Neurosci. Res. 54, 840–84710.1002/(SICI)1097-4547(19981215)54:6<840::AID-JNR12>;2-C
    1. Verge V. M., Gratto K. A., Karchewski L. A., Richardson P. M. (1996). Neurotrophins and nerve injury in the adult. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 351,10.1098/rstb.1996.0038
    1. Wang Q., Hebert S. L., Rich M. M., Kraner S. D. (2011). Loss of synaptic vesicles from neuromuscular junctions in aged MRF4-null mice. Neuroreport 22, 185–18910.1097/WNR.0b013e328344493c
    1. Wang X., Engisch K. L., Li Y., Pinter M. J., Cope T. C., Rich M. M. (2004). Decreased synaptic activity shifts the calcium dependence of release at the mammalian neuromuscular junction in vivo. J. Neurosci. 24, 10687–1069210.1523/JNEUROSCI.2755-04.2004
    1. Wang Z. M., Zheng Z., Messi M. L., Delbono O. (2005). Extension and magnitude of denervation in skeletal muscle from ageing mice. J. Physiol. 565(Pt 3), 757–76410.1113/jphysiol.2005.087601
    1. Weis J., Kaussen M., Calvo S., Buonanno A. (2000). Denervation induces a rapid nuclear accumulation of MRF4 in mature myofibers. Dev. Dyn. 218, 438–45110.1002/1097-0177(200007)
    1. Wenz T., Rossi S. G., Rotundo R. L., Spiegelman B. M., Moraes C. T. (2009). Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging. Proc. Natl. Acad. Sci. U S A. 106, 20405–2041010.1073/pnas.0911570106
    1. Wilson M. H., Deschenes M. R. (2005). The neuromuscular junction: anatomical features and adaptations to various forms of increased, or decreased neuromuscular activity. Int. J. Neurosci. 115, 803–82810.1080/00207450590882172
    1. Witzemann V., Chevessier F., Pacifici P. G., Yampolsky P. (2013). The neuromuscular junction: selective remodeling of synaptic regulators at the nerve/muscle interface. Mech. Dev. 130, 402–41110.1016/j.mod.2012.09.004
    1. Yampolsky P., Pacifici P. G., Witzemann V. (2010). Differential muscle-driven synaptic remodeling in the neuromuscular junction after denervation. Eur. J. Neurosci. 31, 646–65810.1111/j.1460-9568.2010.07096.x
    1. Young K. A., Caldwell J. H. (2005). Modulation of skeletal and cardiac voltage-gated sodium channels by calmodulin. J. Physiol. 565(Pt 2), 349–37010.1113/jphysiol.2004.081422
    1. Yuan Q., Wu W., So K. F., Cheung A. L., Prevette D. M., Oppenheim R. W. (2000). Effects of neurotrophic factors on motoneuron survival following axonal injury in newborn rats. Neuroreport 11, 2237–224110.1097/00001756-200007140-00035
    1. Zhang W., Behringer R. R., Olson E. N. (1995). Inactivation of the myogenic bHLH gene MRF4 results in up-regulation of myogenin and rib anomalies. Genes Dev. 9, 1388–139910.1101/gad.9.11.1388
    1. Zheng Z., Wang Z. M., Delbono O. (2002). Insulin-like growth factor-1 increases skeletal muscle dihydropyridine receptor alpha1s transcriptional activity by acting on the camp-response element-binding protein element of the promoter region. J. Biol. Chem. 277, 50535–5054210.1074/jbc.M210526200

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