Functional impact of sarcopenia in respiratory muscles

Abstract

The risk for respiratory complications and infections is substantially increased in old age, which may be due, in part, to sarcopenia (aging-related weakness and atrophy) of the diaphragm muscle (DIAm), reducing its force generating capacity and impairing the ability to perform expulsive non-ventilatory motor behaviors critical for airway clearance. The aging-related reduction in DIAm force generating capacity is due to selective atrophy of higher force generating type IIx and/or IIb muscle fibers, whereas lower force generating type I and IIa muscle fiber sizes are preserved. Fiber type specific DIAm atrophy is also seen following unilateral phrenic nerve denervation and in other neurodegenerative disorders. Accordingly, the effect of aging on DIAm function resembles that of neurodegeneration and suggests possible common mechanisms, such as the involvement of several neurotrophic factors in mediating DIAm sarcopenia. This review will focus on changes in two neurotrophic signaling pathways that represent potential mechanisms underlying the aging-related fiber type specific DIAm atrophy.

Keywords: Aging; Atrophy; Brain derived neurotrophic factor; Denervation; Diaphragm muscle; Neuregulin.

Fig. 1

Schematic illustrating a fast-twitch fatigable (type FF) and fast-twitch fatigue intermediate (type FInt) motor unit. Muscle fibers corresponding to type FF and FInt motor units are most susceptible to atrophy and weakness secondary to the natural aging process and denervation. Two neurotrophic factors that may be mediating this fiber type specific effect of atrophy and weakness are: (1) brain derived neurotrophic factor (BDNF) acting through the tropomyosin-related kinase receptor B (TrkB) which is involved in motor neuron survival, excitability, and neuromuscular synaptic transmission, and (2) the trophic factor family of neuregulins (NRG) which activate tyrosine kinases of the ErbB receptor family that is released from the motor neuron exerting an anabolic effect on muscle fibers and is implicated in the matching of motor neuron to muscle fiber properties.

Fig. 2

Model of diaphragm muscle motor unit recruitment during ventilatory and non-ventilatory behaviors in mice at 6 and 24 months of age. Motor units are assumed to be recruited in an orderly fashion in rank order beginning with slow-twitch (Type S), followed by fast-twitch fatigue resistant (Type FR), fast-twitch fatigue intermediate (Type FInt), and finally fast-twitch fatigable (Type FF) motor units. Ventilatory behaviors can be accomplished without the recruitment of more fatigable motor units (i.e., FInt and FF). Recruitment of these motor units is only required during more forceful non-ventilatory behaviors that are associated with clearing the airways. Data adapted from (Greising et al., 2015b).

Fig. 3

Diaphragm muscle sarcopenia is event by ~75% survival in mice. (A) Maximal isometric twitch force (P_t ) and maximal tetanic force (P_o ), normalized to physiological cross-sectional area, of midcostal diaphragm muscle (DIAm) of mice across the lifespan (aged 6, 18 and 24 months). There is a significant (*) loss of force by 24 months of age but not between 6 and 18 months. Reprinted with permission from (Greising et al., 2015a). (B) Fiber cross-sectional area (CSA) of the DIAm of across the lifespan. There is a significant (*) loss of type IIx and/or IIb DIAm fiber CSA by 24 months of age. Data at 6 and 24 months of age adapted from (Greising et al., 2013), data at 18 months of age is pilot (n = 4). Mean ± SE.

Fig. 4

Schematic illustrating the aging-related functional consequences of diaphragm muscle (DIAm) fiber type specific sarcopenia (atrophy and weakness). In this model, DIAm sarcopenia is predominantly present in the fast-twitch fatigable (type FF) and fast-twitch fatigue intermediate (type FInt) motor units, which in turn are associated with type IIb and IIx DIAm fibers that express the MyHC_2B and MyHC_2X isoforms, respectively. In contrast, DIAm sarcopenia is less evident in the fast-twitch fatigue resistant (type FR) and slow (type S) motor units, which in turn are associated with type IIa and I DIAm fibers that express the MyHC_2A and MyHC_Slow isoforms, respectively. The functional consequences of this fiber type specific effect of DIAm sarcopenia is a decrease in the maximum transdiaphragmatic pressure (Pdi_max ) the DIAm is capable of generating, and therefore an impaired ability to perform expulsive, high force non-ventilatory behaviors (i.e., coughing and sneezing). However, the Pdi required to perform ventilatory behaviors remains preserved.

Fig. 5

Across the lifespan in mice (aged 6, 18 and 24 months) the contribution of neuromuscular transmission failure to diaphragm muscle fatigue over a 2-min period of repetitive nerve stimulation and superimposed intermittent muscle stimulation. (A) Representative tracings for control (vehicle-treated) diaphragm muscle-phrenic nerve preparations of each age group. (B) Time course of neuromuscular transmission failure during repetitive stimulation in control, brain derived neurotrophic factor (BDNF), or 1NMPP1-treated (inhibition of TrkB kinase activity) preparations at each age group, all for 30 min in vitro. In all age and treatment groups, there is progressively greater neuromuscular transmission failure over time. (C) Neuromuscular transmission failure following 2 min of repetitive stimulation in control, BDNF- and 1NMPP1-treated groups. *Significantly different from control at the same age; †significantly different from BDNF at the same age; ‡significantly different from 6 months within the same treatment; §significantly different from 18 months within the same treatment. Mean ± SE. Reprinted with permission from (Greising et al., 2015a).