Current Aging Science (v.4, #3)

The deterioration of skeletal muscle with advancing age has long been anecdotally recognized as Shakespeare pointed outnearly a half millennium ago in his monologue The Seven Ages of Man [1], and has been of scientific interest for more than 150years [2]. Over the past several decades the scientific and medical communities have recognized that skeletal muscledysfunction (e.g., muscle weakness, muscle atrophy, poor muscle coordination, etc) is a debilitating and life threateningcondition in the elderly. For example, the age-associated loss of muscle strength is highly associated with both mortality andphysical disability [3], and maintenance of muscle mass with advancing age is critical because it serves as a metabolic reservoirthat is needed to effectively withstand disease [4].It is well-accepted that muscle force production results from a combination of neurologic and skeletal muscle factors, andthat biologic properties of both of these systems are altered with aging [5]. Accordingly, the vision for this special issue ofCurrent Aging Science is to provide a series of review articles from internationally recognized experts describing the agerelatedalterations in neuromuscular function and physiology. The first article in this issue will establish the clinical relevanceof age-associated muscle weakness and wasting with respect to physical disability and mortality [6]. Next, a series of articleswill review the age-associated in nerve and muscle form and function, starting at the level of the brain and proceeding down tothe sub-cellular level of individual muscle fibers. Specifically, articles in this issue aim to address age-associated changes in: i)cortical properties and voluntary activation of skeletal muscle [7], ii) motor unit behavioral characteristics [8], motor unit andneuromuscular junction morphology [9], iv) skeletal muscle morphology [10], v) muscle energetics [11], vi) muscle quality andexcitation-contraction coupling processes [12], vii) muscle protein balance and metabolism [13], viii) cell and molecularmechanisms of muscle atrophy [14], ix) satellite cell activity and muscle regeneration [15], and x) endocrine changes and thepotential for therapeutic hormonal interventions to minimize age-associated changes in skeletal muscle [16].I am greatly indebted and would like to expressly thank all of the authors for their outstanding contribution to this issue.Additionally, I would like to thank Current Aging Science (Bentham) and it's Editor-in-Chief, Professor Debomoy K. Lahiri,for providing me the opportunity to pursue this project and develop an entire special issue of this nature. I truly hope thiscollective issue will serve as a centralized resource for the most up-to-date knowledge on age-associated changes inneuromuscular biology and function.

Demographers expect the number of older persons to double to 86.7 million- or to 20.6% of the US population-by the year 2050. As has occurred over the past decade, the health care costs associated with older age are expectedto steadily increase approximately 2% per year causing both a public health and personal burden. A key component to reducinghealth care costs and maintaining well-being in older persons is preserving physical function throughout thelifespan. The challenge to this objective is to combat the origin of the loss of physical function through treatment ofchronic disease conditions. Another approach is to enhance physical function despite the occurrence of comorbid conditionsthrough enhancement of the neuromuscular system. The neuromuscular system provides the necessary componentsfor all locomotion, and is thus a logical choice for preventative therapies to target. This article will give a general overviewof the models and risk factors that explain the development of physical disability.

Aging is associated with dramatic reductions in muscle strength and motor control, and many of these agerelatedchanges in muscle function result from adaptations in the central nervous system. Aging is associated with widespreadqualitative and quantitative changes of the motor cortex. For example, advancing age has been suggested to resultin cortical atrophy, reduced cortical excitability, reduced cortical plasticity, as well as neurochemical abnormalities.Theassociated functional effects of these changes likely influence numerous aspects of muscle performance such as musclestrength and motor control. For example, there is evidence to suggest that the muscle weakness associated with aging ispartially due to impairments in the nervous system's ability to fully activate motor neurons- particularly in the largerproximal muscle groups. In this review article we discuss age-related changes in the motor cortex, as well as the abilityorlack thereof- of older adults to voluntarily activate skeletal muscle. We also provide perspectives on scientific andclinical questions that need to be addressed in the near future.

Alterations in motor unit behavior associated with aging deteriorate fine or gross motor performance. In humanaging, the alterations depend on muscles and the habitual activity of each muscle. This paper will discuss the currentknowledge on the adaptations in major aspects of motor unit behavior including recruitment order, mean and maximaldischarge rate, synchronized discharges, oscillatory discharges, and discharge variability in elderly adults to identify unresolvedproblems. By considering studies on disuse in young adults and training in elderly adults, future research directionsare proposed to help resolve the problems.

The neuromuscular system is one of the largest and most vital organ systems of the body. The function andmass of the neuromuscular system gradually deteriorate during the natural process of aging. The neuromuscular system iscomprised of individual motor units, each of which features a single motor neuron and all the muscle fibers it innervates.Motor units also demonstrate age-related remodeling such as reduced number, muscle fiber atrophy, but an increasednumber of fibers per motor unit. Enabling communication between motor neurons and the muscle fibers they innervate isa specialized synapse known as the neuromuscular junction. Aging, too, elicits remodeling of this synapse joining motornerve terminal endings with a small (< 0.1%) area of the muscle fiber's surface called the endplate. Aged neuromuscularjunctions exhibit elevations in pre-synaptic nerve terminal branching, and in the post-synaptic distribution of receptor sitesfor neurotransmitter. This anatomical remodeling is coupled with age-related neurophysiological alterations including increasedquantal content, with a more rapid rundown of endplate potential strength during continuous stimulation of thepre-synaptic neuron. Moreover, there is a growing body of evidence indicating that aging impacts the capacity of the NMJto adapt to increased, as well as decreased physical activity. Because of the marked increase in the number of people consideredto be aged in industrialized countries, it is essential to expand our understanding of the influence of aging on theneuromuscular system, its constituent motor units, and the neuromuscular junctions which allow neural cells and musclefibers to effectively work together.

Age-Related Changes in Adult Muscle Morphology by Matthew C. Kostek, Matthew J. Delmonico (221-233).
Skeletal muscle undergoes numerous morphological changes from early adulthood to old age including musclesize, configuration, and structure. This review discusses these changes, considers the limitations in interpreting studies,addresses the potential health implications, and describes some mechanisms and interventions to ameliorate aging-relatedchanges in skeletal muscle. Discussion in each section focuses on measurement and analysis techniques of muscle morphology,limitations of human research, and the discussion uses animal work to support findings in humans. We examinethe discrepancies in the study of fiber type distribution with age, and special emphasis is given to two topics: fiber-typedistribution and intra- and intercellular fat. Finally, training adaptations and health implications are briefly discussed. Thefocus of the current review is the morphological changes that occur in skeletal muscle during the normal aging process,with emphasis on human studies.

Properly functioning skeletal muscle is critical for locomotion and performance of many activities of daily living.Muscle wasting and decreased function of skeletal muscle are important factors in many age-related morbidities.There are several pathways for generating ATP in skeletal muscle that allow adequate ATP supply to meet increased demandduring muscle activity. A growing body of literature provides evidence that the aging process may be accompaniedby changes in metabolic supply and demand during muscle contractions. Herein, we review a body of evidence that severalpathways of ATP synthesis (anaerobic glycolysis, oxidative phosphorylation) may be impaired in aging skeletal muscleas well as several underlying molecular and cellular mechanisms. However, detrimental effects of aging on muscle energymetabolism are not universally accepted, particularly when physical inactivity is accounted for. We discuss this importantconcept as well as several potential countermeasures that may compress the period of morbidity in old age. In thesecond half of this review, we discuss how energetic demand of skeletal muscle is affected by aging, with specific focuson basal and contractile ATPase activity.

Functional and structural decline of the neuromuscular system is a recognized cause of decreased strength, impairedperformance of daily living activities, and loss of independence in the elderly. However, in mammals, includinghumans, age-related loss of strength is greater than loss of muscle mass, so the underlying mechanisms remain only partiallyunderstood. This review focuses on the mechanisms underlying impaired skeletal muscle function with aging, includingexternal calcium-dependent skeletal muscle contraction; increased voltage-sensitive calcium channel Cav1.1 ..1asubunitand junctional face protein JP-45 and decreased Cav1.1 (..1) expression, and the potential role of these and otherrecently discovered molecules of the muscle T-tubule/sarcoplasmic reticulum junction in excitation-contraction uncoupling.We also examined neural influences and trophic factors, particularly insulin-like growth factor-I (IGF-1). Better insightinto the triad proteins' involvement in muscle ECC and nerve/muscle interactions and regulation will lead to morerational interventions to delay or prevent muscle weakness with aging. The focus of this review is on the proteins mediatingexcitation-contraction coupling (ECC) and their expression and regulation in humans and rodent models of skeletalmuscle functional decline with aging. Age-dependent changes in proteins other than those related to ECC, muscle composition,clinical assessment and interventions, have been extensively reviewed recently [1-3].

Skeletal Muscle Protein Balance and Metabolism in the Elderly by Christopher S. Fry, Blake B. Rasmussen (260-268).
The loss of lean muscle mass occurring with advancing age is termed sarcopenia. This condition often leads toa concomitant loss of strength, increased frailty and risk of falls and an overall loss of functional independence in the elderly.Muscle protein metabolism is a dynamic process characterized by the balance between the synthesis and breakdownof muscle proteins. A disturbance of this equilibrium can lead to the loss of muscle mass, and a perturbation of muscleprotein turnover with aging has been proposed to play a role in the development of sarcopenia. However, basal muscleprotein synthesis and breakdown rates do not differ between young and old adults, which has led to the hypothesis thatolder adults are resistant to anabolic stimuli. In support of this hypothesis, older adults have either no response or ablunted response to nutrients, insulin and resistance exercise, and this anabolic resistance is likely a key factor in the lossof skeletal muscle mass with aging. Recent studies have investigated potential interventions to overcome this anabolic resistance.In particular, combining resistance exercise with essential amino acid supplementation restores the muscle proteinanabolic response in older men. The novel rehabilitation technique of performing light resistance exercise duringblood flow restriction was also successful in overcoming the anabolic resistance to exercise. Future research is needed todetermine whether these novel interventions will be successful in preventing sarcopenia and improving muscle strengthand function in older adults.

Cellular and Molecular Mechanisms of Apoptosis in Age-Related Muscle Atrophy by Amie J. Dirks-Naylor, Shannon Lennon-Edwards (269-278).
Age-related muscle atrophy is due to loss of muscle fibers as well as atrophy of the remaining fibers. Evidenceshows that loss of myofibers may be, in part, due to apoptosis. Two major apoptotic pathways have been extensively studiedwhich are the mitochondrion-mediated and receptor-mediated pathways. However, other pathways exist, such as thep53 pathway. To date, it is not completely clear what pathways are responsible for loss of fibers in age-related muscle atrophy.Evidence suggests that multiple pathways may play a role. In this review article the effects of aging on the mitochondrion-,receptor-, and p53-mediated apoptotic pathways in skeletal muscle are discussed.

Vertebrate skeletal muscle fibers have two traits that make them unique: the fibers are multinucleated and theirnuclei are post-mitotic. The activity and mass of the muscles in the body make them susceptible to constant injury. Whenthis occurs, myonuclei can be increased or replaced by the adult stem cells of muscle, satellite cells (SCs). These SCs arevital for normal growth, repair and regeneration. This review collates recent studies to determine the size of the nucleardomains and its change with activity. The relationship between the percent change in myonuclear number, cross-sectionalarea, and myonuclear domain indicates that the nucleus generally maintains a highly regulated domain size in spite oflarge variations in fiber size. The SC divides to add nuclei for growth and repair, and the SC identification and number arediscussed. It is concluded that SC number does not reflect a change in regenerative ability by the muscle. However, theSC number increases with changes in muscular activity, and any reduced number of satellite cells in the elderly does notappear to reflect a decline in reparative or regenerative ability. The effects of aging on SC function are reviewed, and thesignificance of the SC's connective tissue environment is emphasized as being a major factor in the decrement of the SC'sability to repair and regenerate the aging muscle. Therefore growth factors and cytokines in the connective tissue aroundthe SC are major influences in the decline of SC function with age.

The Endocrine System and Sarcopenia: Potential Therapeutic Benefits by Kevin L. McIntire, Andrew R. Hoffman (298-305).
Age related muscle loss, known as sarcopenia, is a major factor in disability, loss of mobility and quality of lifein the elderly. There are many proposed mechanisms of age-related muscle loss that include the endocrine system. A varietyof hormones regulate growth, development and metabolism throughout the lifespan. Hormone activity may changewith age as a result of reduced hormone secretion or decreased tissue responsiveness. This review will focus on the complexinterplay between the endocrine system, aging and skeletal muscle and will present possible benefits of therapeuticinterventions for sarcopenia.