Diaphragm muscle sarcopenia in aging mice

Abstract

Sarcopenia, defined as muscle weakness and fiber atrophy, of respiratory muscles such as the diaphragm (DIAm) has not been well characterized. The DIAm is the main inspiratory muscle and knowledge of DIAm sarcopenia is important for establishing the effects of aging on respiratory function. We hypothesized that aging is associated with a loss of DIAm force and reduced fiber cross-sectional area (CSA), and that these changes vary across fiber types. DIAm sarcopenia was assessed in young (5 month; n=11) and old (23 month; n=12) wild-type mice reflecting ~100 and 75% survival, respectively. In addition, DIAm sarcopenia was evaluated in BubR1H/H mice (n=4) that display accelerated aging (~60% survival at 5 months) as a result of expression of a hypomorphic allele (H) of the mitotic checkpoint protein BubR1. Maximum specific force (normalized for CSA) of the DIAm was 34% less in old mice and 57% lower in BubR1H/H mice compared to young mice. Mean CSA of type IIx and/or IIb DIAm fibers was 27% smaller in old wild-type mice and 47% smaller in BubR1H/H mice compared to young mice. Mean CSA of type I or IIa fibers was not different between groups. Collectively these results demonstrate sarcopenia of the DIAm in aging wild-type mice and in BubR1H/H mice displaying accelerated aging. Sarcopenia may limit the ability of the DIAm to accomplish expulsive, non-ventilatory behaviors essential for airway clearance. As a result, these changes in the DIAm may contribute to respiratory complications with aging.

Semi-automated assessment of transdiaphragmatic pressure variability across motor behaviors

“…Studies examining variability in Pdi amplitude across species may thus illuminate differences in variability as they relate to respiratory system mechanics. For example, the higher respiratory frequency and higher proportion of fatigue-resistant fibers in the DIAm of mice compared to rats (Greising et al, 2013a; Prakash and Sieck, 1998; Sieck et al, 2012) is consistent with the relatively smaller fraction of maximal force generating capacity by the DIAm during ventilatory behaviors.…”

Diaphragm abnormalities in heart failure and aging: mechanisms and integration of cardiovascular and respiratory pathophysiology

“…Direct measurements of diaphragm muscle function in vitro and in situ show that isometric force normalized for cross-sectional area (‘specific force’) is depressed by 15–30% in heart failure [74–76,13,77–79] as well as aging [16,15,14,80,81]. The decrease in isometric force is seen in both twitch and maximal tetanic contractions (e.g., Fig.…”

“…The diaphragm is the primary inspiratory muscle and, in CHF, abnormalities of the diaphragm occur earlier or to a greater extent than in limb muscles [9–13]. Similarly, aging causes diaphragm abnormalities [14–16,1]. The combined effects of aging and CHF are unclear because experimental models typically address each condition separately.…”

The challenge of frailty and sarcopenia in heart failure with preserved ejection fraction

“…In an HFpEF rat model, the diaphragm is associated with molecular, mitochondrial, histological and functional alterations, which are different from those of the soleus 21. In addition, ageing is associated with diaphragm muscle weakness and fibre atrophy, which is so-called diaphragm muscle sarcopenia 22. We recently showed that diaphragm muscle atrophy, as assessed by ultrasonography, was accompanied by inspiratory muscle weakness and associated with exercise intolerance in patients with HFpEF 20.…”