Abstract
Ageing and type 2 diabetes mellitus (T2DM) are risk factors for skeletal muscle loss. We investigated whether anabolic resistance to feeding might underlie accelerated muscle loss in older people with T2DM and whether dysregulated mTOR signalling was implicated. 8 obese men with T2DM, and 12 age-matched controls were studied (age 68±3 vs. 68±6y; BMI: 30±2 vs. 27±5kgm-2). Body composition was measured by dual-X-ray absorptiometry. Insulin and glucose were clamped at post-absorptive concentrations (13±2 vs. 9±3mUl-1; 7.4±1.9 vs. 4.6±0.4mmoll-1; T2DM vs. controls). Fractional synthetic rates (FSR) of myofibrillar and sarcoplasmic proteins were measured as the rate of incorporation of [13C] leucine during a primed, constant infusion of [1-13C] α-ketoisocaproic acid, 3h after 10 or 20g of essential amino acids (EAA) were orally administered. Protein expression of total and phosphorylated mTOR signalling proteins was determined by Western blot analysis. Despite a significantly lower appendicular lean mass index and a greater fat mass index in T2DM vs. controls, basal myofibrillar and sarcoplasmic and post-prandial myofibrillar FSR were similar. After 20g EAA, stimulation of sarcoplasmic FSR was slightly blunted in T2DM patients. Furthermore, feeding 20g EAA increased phosphorylation of mTOR, p70S6k and 4E-BP1 by 60-100% in controls with no response observed in T2DM. There was clear dissociation between changes in mTOR signalling versus changes in protein synthesis rates. However, the intact anabolic response of myofibrillar FSR to feeding in both groups suggests anabolic resistance may not explain accelerated muscle loss in T2DM.
Highlights
Sarcopenia is characterised by a progressive decline in skeletal muscle mass resulting in low muscle strength and impaired physical performance [1]
We determined whether an impaired anabolic response to feeding (with essential amino acids, (EAA)) was evident in skeletal muscle of older patients with T2D and whether diminished anabolic sensing and signalling through the PKB/mammalian target of rapamycin (mTOR) pathway was implicated in any impairment
We have shown that in obese older patients with type 2 diabetes mellitus (T2DM) and good glycaemic control, rates of myofibrillar or sarcoplasmic muscle protein synthesis were similar to those in age-matched, nondiabetic individuals
Summary
Sarcopenia is characterised by a progressive decline in skeletal muscle mass resulting in low muscle strength and impaired physical performance [1]. The biological mechanisms associated with accelerated loss of muscle remain uncertain but alterations in skeletal muscle protein turnover are clearly implicated in such modifications in T2DM with evidence of impaired stimulation of protein synthesis related to ageing and insulin resistance [3,4]. We determined whether an impaired anabolic response to feeding (with essential amino acids, (EAA)) was evident in skeletal muscle of older patients with T2D and whether diminished anabolic sensing and signalling through the PKB/mTOR pathway was implicated in any impairment. We investigated whether anabolic resistance to feeding might underlie accelerated muscle loss in older people with T2DM and whether dysregulated mTOR signalling was implicated. The intact anabolic response of myofibrillar FSR to feeding in both groups suggests anabolic resistance may not explain accelerated muscle loss in T2DM
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