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). The role of neural factors in regulating the
expression and function of these newly identified triad proteins is a necessary focus
of research in the coming years. We hypothesize that neural factors (autocrine
127Excitation-Contraction Coupling Regulation in Aging Skeletal Muscle
trophic factors, nerve activity and connectivity) play a vital role in preventing
age-related excitation-contraction uncoupling. Based on this hypothesis, we predict
that interventions aimed at counteracting nerve loss will play an important part in
ameliorating the loss of force exhibited in animal models of aging as well as in
elderly humans.
Acknowledgments Results reported in this article were obtained with the support of the National
Institutes of Health/National Institute on Aging (AG15820, AG13934, and AG033385) and
Muscular Dystrophy Association of America’s grants to Osvaldo Delbono and the Wake Forest
University Claude D. Pepper Older Americans Independence Center (P30-AG21332).
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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:
Alterations in Mitochondria and Their
Impact in Aging Skeletal Muscle
Russell T. Hepple