The age-related loss of skeletal muscle mass and function: Measurement and physiology of muscle fibre atrophy and muscle fibre loss in humans

Abstract

Age-related loss of skeletal muscle mass and function, sarcopenia, is associated with physical frailty and increased risk of morbidity (chronic diseases), in addition to all-cause mortality. The loss of muscle mass occurs incipiently from middle-age (∼1%/year), and in severe instances can lead to a loss of ∼50% by the 8-9th decade of life. This review will focus on muscle deterioration with ageing and highlight the two underpinning mechanisms regulating declines in muscle mass and function: muscle fibre atrophy and muscle fibre loss (hypoplasia) - and their measurement. The mechanisms of muscle fibre atrophy in humans relate to imbalances in muscle protein synthesis (MPS) and breakdown (MPB); however, since there is limited evidence for basal alterations in muscle protein turnover, it would appear that "anabolic resistance" to fundamental environmental cues regulating diurnal muscle homeostasis (namely physical activity and nutrition), underlie age-related catabolic perturbations in muscle proteostasis. While the 'upstream' drivers of the desensitization of aged muscle to anabolic stimuli are poorly defined, they most likely relate to impaired efficiency of the conversion of nutritional/exercise stimuli into signalling impacting mRNA translation and proteolysis. Additionally, loss of muscle fibres has been shown in cadaveric studies using anatomical fibre counts, and from iEMG studies demonstrating motor unit loss, albeit with few molecular investigations of this in humans. We suggest that defining countermeasures against sarcopenia requires improved understandings of the co-ordinated regulation of muscle fibre atrophy and fibre loss, which are likely to be inextricably linked.

Keywords: Anabolic resistance; Atrophy; Denervation; Hypoplasia; Muscle; Sarcopenia.

Fig. 1

Summary of the purported mechanisms driving anabolic resistance and muscle atrophy in older age. In young adult muscle the response to anabolic stimuli such as mechanical sensing and feeding, provides stimulation of MPS and inhibition of MPB regulated primarily via control through mTORc1 signalling helping to maintain muscle mass. In older age, muscle becomes resistance to these anabolic stimuli, leading to impaired MPS and suppressed inhibition of MPB, consequently leading to the onset of atrophy. The factors driving this anabolic resistance and atrophy are not well described, however a number of theories have been proposed as highlighted in the figure and discussed within this review.

Fig. 2

Summary of denervation induced muscle fibre hypoplasia Top: With normal innervation, myelinated axons communicate with the muscle fibre at the NMJ. Each neuron and all muscle fibres connected to it via the NMJ are part of the same MU. Denervated fibres may be reinnervated by schwann cell guided axonal sprouting, or they may atrophy and eventually be lost. Bottom: With normal innervation, electrical activity from action potentials suppress NMJ maintenance genes in non-synaptic nuclei, with expression maintained in synaptic nuclei via agrin-MuSK signalling. Immediately post denervation proteasomal degradation is increased, then decreased with prolonged denervation combined with an increase in protein synthesis.