Age‐related differences in lean mass, protein synthesis and skeletal muscle markers of proteolysis after bed rest and exercise rehabilitation

Abstract

Key pointsr Five days of bed rest resulted in a reduction in leg lean mass and strength in older adults. r After bed rest, older (but not younger) adults had reduced amino acid-induced anabolic sensitivity (blunted muscle protein synthesis; MPS) and enhanced markers associated with the ubiquitin proteasome and autophagy-lysosomal systems (increase in molecular markers related to muscle proteolysis).r Younger adults did not lose leg lean mass (via DXA) after 5 days of bed rest despite blunted amino acid-induced mTORC1 signalling and increased skeletal muscle REDD1, REDD2 and MURF1 mRNA expression.r Exercise rehabilitation restored bed rest-induced deficits in lean mass, strength, nutrient-induced protein anabolism (protein synthesis and mTORC1 signalling) and select muscle proteolytic markers in older adults.Abstract Bed rest-induced muscle loss and impaired muscle recovery may contribute to age-related sarcopenia. It is unknown if there are age-related differences in muscle mass and muscle anabolic and catabolic responses to bed rest. A secondary objective was to determine if rehabilitation could reverse bed rest responses. Nine older and fourteen young adults participated in a 5-day bed rest challenge (BED REST). This was followed by 8 weeks of high intensity resistance exercise (REHAB). Leg lean mass (via dual-energy X-ray absorptiometry; DXA) and strength were determined. Muscle biopsies were collected during a constant stable isotope infusion in the postabsorptive state and after essential amino acid (EAA) ingestion on three occasions: before (PRE), after bed rest and after rehabilitation. Samples were assessed for protein synthesis, mTORC1 signalling, REDD1/2 expression and molecular markers related to muscle proteolysis (MURF1, MAFBX, AMPKα, LC3II/I, Beclin1). We found that leg lean mass and strength decreased in older but not younger adults after bedrest (P < 0.05) and was restored after rehabilitation. EAA-induced mTORC1 signalling and protein synthesis increased before bed rest in both age groups (P < 0.05). Although both groups had blunted mTORC1 signalling, increased REDD2 and MURF1 mRNA after bedrest, only older adults had reduced EAA-induced protein synthesis rates and increased MAFBX mRNA, p-AMPKα and the LC3II/I ratio (P < 0.05). We conclude that older adults are more susceptible than young persons to muscle loss after short-term bed rest. This may be partially explained by a combined suppression of protein synthesis and a marginal increase in proteolytic markers. Finally, rehabilitation restored bed rest-induced deficits in lean mass and strength in older adults.

Emerging role for regulated in development and DNA damage 1 (REDD1) in the regulation of skeletal muscle metabolism

“…Following a post-bed rest 8-wk rehabilitation program consisting of high-intensity eccentric contractions, REDD1 mRNA in young subjects was no longer increased relative to baseline measures, and REDD1 mRNA was reduced in older subjects to values below those observed in the young subjects (121). Furthermore, the amino acid-induced phosphorylation of p70S6K1 (Thr 389 ) was restored following rehabilitation in both the young and old participants, and the amino acid-induced rate of mixed muscle protein synthesis was again increased in the old subjects (121). These data suggest that the increase in REDD1 mRNA in older subjects at baseline was not associated with blunted stimulation of mTORC1 or protein synthesis by nutrients and that the bed rest-induced resistance to amino acid-induced phosphorylation of p70S6K1 and protein synthesis in older subjects was independent of changes in REDD1 mRNA.…”

“…Amino acidinduced phosphorylation of p70S6K1 (Thr 389 ) was blunted in both groups following bedrest, whereas phosphorylation of 4E-BP1 (Thr 37/46 ) was increased appropriately in both groups (121). Despite similar alteration in amino acid-induced stimulation of mTORC1 signaling following bed rest, mixed muscle protein synthesis was increased only in the young subjects despite increased REDD1 mRNA (121). Following a post-bed rest 8-wk rehabilitation program consisting of high-intensity eccentric contractions, REDD1 mRNA in young subjects was no longer increased relative to baseline measures, and REDD1 mRNA was reduced in older subjects to values below those observed in the young subjects (121).…”

“…Baseline measurements taken prior to bedrest indicated that older subjects had greater REDD1 mRNA that did not coincide with blunted amino acid-induced stimulation of mTORC1 or mixed muscle protein synthesis. Amino acidinduced phosphorylation of p70S6K1 (Thr 389 ) was blunted in both groups following bedrest, whereas phosphorylation of 4E-BP1 (Thr 37/46 ) was increased appropriately in both groups (121). Despite similar alteration in amino acid-induced stimulation of mTORC1 signaling following bed rest, mixed muscle protein synthesis was increased only in the young subjects despite increased REDD1 mRNA (121).…”

“…Despite similar alteration in amino acid-induced stimulation of mTORC1 signaling following bed rest, mixed muscle protein synthesis was increased only in the young subjects despite increased REDD1 mRNA (121). Following a post-bed rest 8-wk rehabilitation program consisting of high-intensity eccentric contractions, REDD1 mRNA in young subjects was no longer increased relative to baseline measures, and REDD1 mRNA was reduced in older subjects to values below those observed in the young subjects (121). Furthermore, the amino acid-induced phosphorylation of p70S6K1 (Thr 389 ) was restored following rehabilitation in both the young and old participants, and the amino acid-induced rate of mixed muscle protein synthesis was again increased in the old subjects (121).…”

From physical inactivity to immobilization: Dissecting the role of oxidative stress in skeletal muscle insulin resistance and atrophy

“…The muscle RING finger 1 (MurF1) and muscle atrophy F-box (MAFbx) are the main ubiquitin ligases responsible for protein degradation in skeletal muscle. It is well established that immobilization causes an accumulation of polyubiquitinated proteins in rodent and human skeletal muscle [96][97][98] due to increase in both MuRF-1 and MAFbx expression [53,57,62,99]. The nuclear factor-κB (NF-κB) directly regulates the transcription of MuRF1, and consequently plays an important role in immobilization-induced protein degradation [100,101].…”