Sarcopenia. Группа авторов

CHAPTER 4 Motor Unit Remodeling

       Ben Kirk1,2 and Mathew Piasecki3

       ¹ Department of Medicine, Western Health, Melbourne Medical School, University of Melbourne, St Albans, Melbourne, VIC, Australia

       ² Australian Institute for Musculoskeletal Science (AIMSS), University of Melbourne and Western Health, St Albans, Melbourne, VIC, Australia

       ³ Clinical, Metabolic and Molecular Physiology, MRC Versus Arthritis Centre for Musculoskeletal Ageing Research, Nottingham Biomedical Research Centre, University of Nottingham, Nottingham, UK

OVERVIEW OF THE NEUROMUSCULAR SYSTEM

      To fully appreciate the contribution of motor unit (MU) remodeling to sarcopenia, a reminder of the basic structure and function of the neuromuscular system is described. The human body is made up of over 500 skeletal muscles [1]. Each individual MU consists of a neuron, its axon and the muscle fibers it innervates. Wrapping around the axon are Schwann cells to form a myelinated sheath and promote the conduction of motor nerve action potentials. In the limited space between the motor neuron terminal and the muscle fiber, sits the neuromuscular junction. This junction, or chemical synapse, allows signals to be translated from neurons to muscle cells via neurotransmitter release and receptor binding.

      At the structural level, there are three types of muscle fibers involved in contraction: type I, type IIa, and type IIx. These phenotypes contain differing physiological properties; for example, type I fibers (slow‐twitch) are highly oxidative and possess a low capacity to generate adenosine triphosphate (ATP). In comparison, type IIa fibers are fast‐twitch, carry high ATP and glycolytic capacity, and are fatigue resistant. Type IIx fibers (also fast‐twitch) have the highest ATP generating capacity but lowest glycolytic capacity and fatigue rapidly [2]. Notably, many fibers can express more than one isoform of myosin heavy chain (MHC) and are referred to as hybrid fibers. Stacks of muscle fibers (known as myofibrils), contain sarcomeres and are made up of two main contractile proteins: actin (thin) and myosin (thick). Each myosin is made up of two myosin heads arranged longitudinally with ATP and actin binding sites. Actin, like myosin, has a double helix structure; however, it has additional protein structures, namely troponin and tropomyosin. The former enables calcium (Ca²⁺) to bind, while the latter blocks the binding site of actin.

The nervous system regulates MU recruitment and allows an older adult to carry out a range of movements from fast and powerful (i.e., stairs climbing) to small and subtle (writing). To enable this energy dependent process, action potentials are first generated in the motor cortex of the brain and are then transmitted via the spinal cord into the MU pool. At the peripheral level, this action potential further propagates down motor axons to the neuromuscular junction (NMJ), then throughout muscle fibers down into the transverse tubular system, which in turn, activates ryanodine receptors causing the release of Ca²⁺ ions from the sarcoplasmic reticulum and enables structural proteins to contract. These electrophysiological processes are highly energy dependent and any disruption to the structure or function of MU will impede force production.

AGE‐RELATED MU REMODELING

      Loss of MUs

      Adaptations to the neuromuscular system are marked by aging and are evidenced by direct quantification of MUs from human cadavers or indirectly by estimating MU numbers via electrophysiological techniques.

      Early postmortem work shows a substantial reduction in the number of motor neurons (around 30–50%) in the lumber spine of older (>60 years) compared with younger adults [3]. Around the same time, two more cadaver studies demonstrated a decrease in motor neurons serving muscle fibers in the lower spinal region [4, 5]. Myoelectrical examination of various anatomical muscles have added to this body of knowledge. The estimated number of MU in the tibialis anterior, a key dorsiflexor, progressively decreases from young (~25 years [150 MUs]) to old (~65 years [91 MUs]) men, and further declines in the oldest men (~85 years [59 MUs]) [6]. Numerous other studies corroborate this loss of MU in upper (biceps brachii) [7] and lower limb (vastus lateralis) [8] muscles when comparing older adults with their younger counterparts. Although MU numbers have been reported with clear differences between young and old, MU number estimate techniques are limited by muscle size and electrode detection area, likely explaining the remarkably similar MU numbers reported for muscles of vastly different sizes (e.g. 138 in the first dorsal interosseous [9] and 195 in the VL [8]). Therefore, these methods should be viewed as an index rather than a true anatomical count.

      A recent review of the literature also noted that by the seventh decade of life, healthy older adults have around 40% fewer MUs [10] than young. Of note, these studies have been conducted in healthy older adults, which demonstrates that neuromuscular remodeling is, to some degree, an unavoidable physiological consequence of aging. A recent review [11] further discusses the neuromuscular adaptions that occur even in states of healthy aging.

Until recently, the direct role of MU remodeling in the pathophysiology of sarcopenia was unknown. Although findings from immunosenescent studies of animal models showed that apoptosis of motor neurons and subsequent denervation of muscle fibers leads to muscle weakness in diseases which overlap with sarcopenia [12]. Compelling work by Piasecki and colleagues [13] was the first to quantify MUs across healthy young, non‐sarcopenic old, pre‐sarcopenic older, and sarcopenic older men. Unsurprisingly, muscle mass (8, 30, 44%), MU number (33, 47, 50%), and maximal strength (34, 39, 49%) were significantly lower in non‐sarcopenic old, pre‐sarcopenic older, and sarcopenic older men, respectively, in comparison with the younger reference group [12]. Moreover, MU potentials recorded with intramuscular needle electrodes were larger by 26 and 41% in non‐sarcopenia and pre‐sarcopenic older men, respectively, and were similar to young in the sarcopenic older men. Taken together this suggests “healthier” older men can reinnervate larger bundles of muscle fibers to counteract the loss of motor neurons with age, but this process may fail and contribute to the sarcopenic condition via muscle fiber loss [13]. This phenomenon, known as the denervation–reinnervation cycle, or MU remodeling (Figure 4.1), is a likely explanation for the increased size of MU observed in upper‐and lower‐limb locomotory muscles [15–19] of previous studies in older adults. Others have also noted that the remaining MUs in an aged muscle are enlarged by around 50% [10]. Indeed,