126 O. Delbono These studies suggest that IGF-1 might have beneficial effects on spinal cord motor neurons from senescent mammals. However, transgenic overexpression of IGF-1 in the central nervous system does not improve excitation-contraction cou- pling or neuromuscular performance in the mouse (Ye et al. 1996; Moreno et al. 2006). In contrast to localized motor neuron expression, widespread IGF-1 may be deleterious for neuronal function or muscle innervation (Moreno et al. 2006). During embryonic and postnatal development, specific sets of CNS neurons show high levels of IGF-1 receptor gene expression combined with IGF-1 expres- sion, while in hippocampal and cortical neurons, receptor and IGF-1 expression are localized in different cell groups (Bondy et al. 1992). These expression patterns suggest that IGF-1 exerts autocrine and paracrine effects in the CNS in addition to its previously described paracrine (muscle-derived) actions on spinal cord motor neurons. While these mechanisms contribute undoubtedly to the development of the appropriate neuronal phenotype and probably to its maintenance in adulthood, its involvement in aging processes remains substantially untested. Despite these uncertainties, an age-related decline in neuronal as well as muscle-derived IGF-1 combined with altered IGF-1 resistance through reduced expression or sensitivity of the receptor may contribute to the atrophy or death of motor and other CNS neurons in aging mammals. Through the previously described mechanisms, these changes may trigger a cascade of events leading to decreased skeletal muscle gene transcription. 10 Concluding Remarks Age-related decline in the neuromuscular system is a recognized cause of impaired physical performance and loss of independence in the elderly. Epidemiological data associate these changes with increased risk of morbidity, disability, and mortality in the elderly (Winograd et al. 1991; Baumgartner et al. 1998; Ryall et al. 2008). We argue for the importance of neural factors in age-related impairment of mammalian skeletal muscle structure and function. Decreased local production of IGF-1 and/or neurotrophins and tissue resistance to these factors through altered receptor expression or responsiveness may result in loss and atrophy of spinal cord motor neurons. In fact, declining motor neuron function may be more extensive than that predicted by structural assays. Preliminary data support the concept that reduced IGF-1 synthesis may cause the failure of an IGF-mediated pathway to decrease CREB phosphorylation. In turn, reduced CREB phosphorylation may result in reduced DHPRa 1S transcription, excitation-contraction uncoupling, and decreased muscle force. The characterization of a number of triad proteins is shedding light on the molec- ular signaling involved in excitation-gene expression and excitation- contraction coupling (Carrasco et al. 2004). 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Charge movement and transcription regulation of L-type calcium channel alpha-1S in skeletal muscle cells. Journal of Physiology, 540, 397–409. 135 G.S. Lynch (ed.), Sarcopenia – Age-Related Muscle Wasting and Weakness, DOI 10.1007/978-90-481-9713-2_7, © Springer Science+Business Media B.V. 2011 Abstract There is an abundance of studies examining the involvement of mitochondria in aging, including their role in the functional and structural deterioration of skeletal muscle with aging. Despite years of study, the precise involvement of mitochondria in the aging of skeletal muscle remains to be fully understood. This chapter provides some context for the current knowledge in this area and areas that will be refined through further study. It will examine the issue of “mitochondrial dysfunction” in aging; why it occurs and the functional consequences. The potential impact of three important age-related changes in mitochondria will be considered here: a reduced capacity for generating cellular energy in the form of adenosine triphosphate (ATP); an increased susceptibility to apoptosis; and an increase in reactive oxygen species (ROS) production with aging. The chapter considers the extent to which the mitochondrial content may be up-regulated in response to muscle activity as a means of assessing the malleability of the age-related impairments in mitochondria. Given the central importance of mitochondrial biology to so many facets of normal cell function, particularly in tissues with a wide metabolic scope like skeletal muscle, new discoveries about the significance of changes in mitochondria for aging skeletal muscles, and their potential remedy through lifestyle modification (e.g., exercise training, diet) and/ or medical intervention (e.g., pharmaceuticals, gene therapy), will remain at the forefront of our quest to promote healthy aging. Keywords Apoptosis • Denervation • Exercise • Mitochondria • Mitochondrial biogenesis • Mitochondrial dysfunction • Plasticity • Reactive oxygen species R.T. Hepple () Faculty of Kinesiology and Faculty of Medicine University of Calgary, Calgary, Canada e-mail: hepple@ucalgary.ca Alterations in Mitochondria and Their Impact in Aging Skeletal Muscle Russell T. Hepple . fast- and slow-fibers from mouse EDL and soleus skeletal muscles. Mechanisms of Ageing and Development, 122, 1019–1032. 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