The impact of immobilisation and inflammation on the regulation of muscle mass and insulin resistance: different routes to similar end‐points

Abstract

Loss of muscle mass and insulin sensitivity are common phenotypic traits of immobilisation and increased inflammatory burden. The suppression of muscle protein synthesis is the primary driver of muscle mass loss in human immobilisation, and includes blunting of post-prandial increases in muscle protein synthesis. However, the mechanistic drivers of this suppression are unresolved. Immobilisation also induces limb insulin resistance in humans, which appears to be attributable to the reduction in muscle contraction per se. Again mechanistic insight is missing such that we do not know how muscle senses its "inactivity status" or whether the proposed drivers of muscle insulin resistance are simply arising as a consequence of immobilisation. A heightened inflammatory state is associated with major and rapid changes in muscle protein turnover and mass, and dampened insulin-stimulated glucose disposal and oxidation in both rodents and humans. A limited amount of research has attempted to elucidate molecular regulators of muscle mass loss and insulin resistance during increased inflammatory burden, but rarely concurrently. Nevertheless, there is evidence that Akt (protein kinase B) signalling and FOXO transcription factors form part of a common signalling pathway in this scenario, such that molecular cross-talk between atrophy and insulin signalling during heightened inflammation is believed to be possible. To conclude, whilst muscle mass loss and insulin resistance are common end-points of immobilisation and increased inflammatory burden, a lack of understanding of the mechanisms responsible for these traits exists such that a substantial gap in understanding of the pathophysiology in humans endures.

Perioperative nutrition: Recommendations from the ESPEN expert group

“…There are significant metabolic changes associated with a period of bedrest which are paralleled in the metabolic changes occurring after surgery [44] as immobilization is one of the key components of postoperative changes. These negative changes are also observed in clinical populations and sarcopenic or frail older adults [45] and include a decline in basal energy expenditure, reduced insulin sensitivity, anabolic resistance to protein nutrition, muscle strength and physical performance as well as increased risk of falls, healthrelated expenditure, morbidity and mortality.…”

“…However, robust voluntary exercise intervention postoperatively at a time when metabolic dysregulation and fatigue are at their greatest is unlikely to be practicable, and fatigue may persist for many weeks after surgery [167]. Furthermore, muscle wasting and deconditioning will be exacerbated by prolonged periods of bed rest [44]. In this situation, non-voluntary, transcutaneous, electrically evoked muscle contraction may be an effective strategy for the maintaining or improving muscle mass and function after surgery until voluntary exercise, which is likely to be most effective, is practicable [168].…”

Effect of flaxseed oil on muscle protein loss and carbohydrate oxidation impairment in a pig model after lipopolysaccharide challenge

“…Pro-inflammatory cytokines can lead to muscle protein loss directly or via alterations of the Akt/FOXO/ubiquitin-proteasome pathway. Akt/FOXO is a common signalling pathway influencing muscle protein breakdown and synthesis during inflammation (51) . Phosphorylation and inactivation of FOXO1 induced by Akt1 activation can suppress muscle proteolysis and muscle atrophy by transcriptional inhibition of FOXO target genes such as MAFbx and MuRF1; the latter are the main regulators in protein degradation in skeletal muscle (52) .…”

Regulation of musculoskeletal tissues in ageing and health: the human perspective – Celebrating the research of Professor Mike Rennie

“…), and ‘The impact of immobilisation and inflammation on the regulation of muscle mass and insulin resistance: different routes to similar end points’ by Hannah Crossland, Sarah Skirrow, Zudin Puthucheary, Dumitru Constantin‐Teodosiu and Paul Greenhaff (Crossland et al . ). The topic of physiological adaptation of musculoskeletal tissues to mechanoloading is extended to cartilage in the paper ‘Mechanoadaptation: articular cartilage through thick and thin’ by Tonia Vincent and Angus Wann (Vincent & Wann, ).…”