Short‐term disuse does not affect postabsorptive or postprandial muscle protein fractional breakdown rates

Abstract

BackgroundThe decline in postabsorptive and postprandial muscle protein fractional synthesis rates (FSR) does not quantitatively account for muscle atrophy during uncomplicated, short‐term disuse, when atrophy rates are the highest. We sought to determine whether 2 days of unilateral knee immobilization affects mixed muscle protein fractional breakdown rates (FBR) during postabsorptive and simulated postprandial conditions.MethodsTwenty‐three healthy, male participants (age: 22 ± 1 year; height: 179 ± 1 cm; body mass: 73.4 ± 1.5 kg; body mass index 22.8 ± 0.5 kg·m−2) took part in this randomized, controlled study. After 48 h of unilateral knee immobilization, primed continuous intravenous l‐[15N]‐phenylalanine and l‐[ring‐2H5]‐phenylalanine infusions were used for parallel determinations of FBR and FSR, respectively, in a postabsorptive (saline infusion; FAST) or simulated postprandial state (67.5 mg·kg body mass−1·h−1 amino acid infusion; FED). Bilateral m. vastus lateralis biopsies from the control (CON) and immobilized (IMM) legs, and arterialized‐venous blood samples, were collected throughout.ResultsAmino acid infusion rapidly increased plasma phenylalanine (59 ± 9%), leucine (76 ± 5%), isoleucine (109 ± 7%) and valine (42 ± 4%) concentrations in FED only (all P < 0.001), which was sustained for the remainder of infusion. Serum insulin concentrations peaked at 21.8 ± 2.2 mU·L−1 at 15 min in FED only (P < 0.001) and were 60% greater in FED than FAST (P < 0.01). Immobilization did not influence FBR in either FAST (CON: 0.150 ± 0.018; IMM: 0.143 ± 0.017%·h−1) or FED (CON: 0.134 ± 0.012; IMM: 0.160 ± 0.018%·h−1; all effects P > 0.05). However, immobilization decreased FSR (P < 0.05) in both FAST (0.071 ± 0.004 vs. 0.086 ± 0.007%·h−1; IMM vs CON, respectively) and FED (0.066 ± 0.016 vs. 0.119 ± 0.016%·h−1; IMM vs CON, respectively). Consequently, immobilization decreased net muscle protein balance (P < 0.05) and to a greater extent in FED (CON: −0.012 ± 0.025; IMM: −0.095 ± 0.023%·h−1; P < 0.05) than FAST (CON: −0.064 ± 0.020; IMM: −0.072 ± 0.017%·h−1).ConclusionsWe conclude that merely 2 days of leg immobilization does not modulate postabsorptive and simulated postprandial muscle protein breakdown rates. Instead, under these conditions the muscle negative muscle protein balance associated with brief periods of experimental disuse is driven near exclusively by reduced basal muscle protein synthesis rates and anabolic resistance to amino acid administration.

Downregulation of NR4A3 during inactivity alters glucose metabolism and impairs translation in human skeletal muscle

“…We next investigated the impact of NR4A3 downregulation on markers of protein degradation. Although the contribution of protein breakdown towards disuse muscle atrophy is unclear in humans [2, 12], the ubiquitin-proteasomal (UPS) and autophagy-lysosomal systems are markedly induced during rodent models of inactivity [18, 19]. Additionally, skeletal muscle-specific NR4A3 transgenic mice display greater autophagic flux [42].…”

“…Detriments in both mTORC1 [9] and ribosomal abundance [10] are observed in human skeletal muscle with inactivity. Alongside insulin- and amino acid-resistance [2, 9, 11, 12], this downregulation of translational machinery drives initial losses in muscle mass through dampened myofibrillar protein synthetic responses [2, 12]. As a transducer of the phosphatidylinositol-3-kinase (PI3K)-AKT pathway, mTORC1 is also central to muscle proteostasis via temporal coordination of anabolic and catabolic processes [13].…”

Skeletal muscle immobilisation-induced atrophy: mechanistic insights from human studies

“…The aforementioned blunted anabolic response to protein/amino acid feeding is known as ‘anabolic resistance’. MPB, on the other hand, either remains unchanged [ 54 , 56 , 57 ] or has been shown to decline [ 55 , 56 ], suggesting that bulk MPB does not appreciably contribute to disuse muscle atrophy in post-pubertal humans, which is also supported by mathematical estimates [ 58 ]. Deficits in fasted/fed MPS, as opposed to increases in MPB, should be considered the driving force of immobilisation-induced atrophy in humans in being sufficient in itself to explain muscle mass lost [ 57 , 59 ].…”

“…MPB, on the other hand, either remains unchanged [54,56,57] or has been shown to decline [55,56], suggesting that bulk MPB does not appreciably contribute to disuse muscle atrophy in post-pubertal humans, which is also supported by mathematical estimates [58]. Deficits in fasted/fed MPS, as opposed to increases in MPB, should be considered the driving force of immobilisation-induced atrophy in humans in being sufficient in itself to explain muscle mass lost [57,59]. This may be caveated in that disease-associated muscle atrophy could be a consequence of decreased MPS and increased MPB due to prevailing systemic factors, e.g., circulating cytokines and cortisol, commonly associated with disease's (e.g.…”

The impact of forearm immobilization and acipimox administration on muscle amino acid metabolism and insulin sensitivity in healthy, young volunteers

“…Perturbations in muscle lipid handling have been suggested to underpin the development of anabolic and insulin resistance during muscle disuse. We have previously demonstrated that a shift toward positive nonesterified fatty acid (NEFA) balance occurs across the forearm in response to ingestion of a mixed meal after 2 and 7 days of immobilization, which corresponded with insulin ( 10 ) and anabolic ( 5 , 6 , 12 ) resistance. Presumably this positive balance results in lipid accumulation within the muscle during disuse.…”