A neuromuscular perspective of sarcopenia pathogenesis: deciphering the signaling pathways involved

Abstract

The escalation of life expectancy is accompanied by an increase in the prevalence of age-related conditions, such as sarcopenia. Sarcopenia, a muscle condition defined by low muscle strength, muscle quality or quantity, and physical performance, has a high prevalence among the elderly and is associated to increased mortality. The neuromuscular system has been emerging as a key contributor to sarcopenia pathogenesis. Indeed, the age-related degeneration of the neuromuscular junction (NMJ) function and structure may contribute to the loss of muscle strength and ultimately to the loss of muscle mass that characterize sarcopenia. The present mini-review discusses important signaling pathways involved in the function and maintenance of the NMJ, giving emphasis to the ones that might contribute to sarcopenia pathogenesis. Some conceivable biomarkers, such as C-terminal agrin fragment (CAF) and brain-derived neurotrophic factor (BDNF), and therapeutic targets, namely acetylcholine and calcitonin gene-related peptide (CGRP), can be retrieved, making way to future studies to validate their clinical use.

Keywords: BDNF; CAF; Denervation; Muscle wasting; Neuromuscular junction; Neurotrophins.

Fig. 1

The age-induced alterations that seem to preclude sarcopenia. Changes in the levels of key neuromuscular system–related mediators associated to the impairment of the neuromuscular junction function and morphology are highlighted as well as alterations in signal transmission between the motoneurons and muscle fibers, and of the reinnervation process that culminate in impaired muscle function. The mediators analyzed in the serum in aging or sarcopenia contexts are preceded by “s”, while the ones not analyzed in these contexts (but in other conditions) are preceded by “(s)”. Figure produced with Servier Medical Art. Abbreviations: ACh: acetylcholine; AChE: acetylcholinesterase; AChR: acetylcholine receptor; BDNF: brain-derived neurotrophic factor; CAF: C-terminal agrin fragment; CGRP: calcitonin gene–related protein; CLR: calcitonin-like receptor; DOK7: downstream of kinase 7; GAP-43: growth-associated protein; GDNF: glial-cell-line-derived neurotrophic factor; GFRα1: glial-cell-line-derived neurotrophic factor family receptor alpha 1; LRP4: low-density lipoprotein receptor–related protein 4; MuSK: muscle-specific kinase; NCAM: neural cell adhesion molecule; SCs: satellite cells; SNAP-25: synaptosomal-associated protein of 25 kDa; TrkB: tropomyosin-related kinase; VGCC: voltage-gated calcium channel