Abnormal protein turnover and anabolic resistance to exercise in sarcopenic obesity

Abstract

Obesity may impair protein synthesis rates and cause anabolic resistance to growth factors, hormones, and exercise, ultimately affecting skeletal muscle mass and function. To better understand muscle wasting and anabolic resistance with obesity, we assessed protein 24-h fractional synthesis rates (24-h FSRs) in selected hind-limb muscles of sedentary and resistance-exercised lean and obese Zucker rats. Despite atrophied hind-limb muscles (-28% vs. lean rats), 24-h FSRs of mixed proteins were significantly higher in quadriceps (+18%) and red or white gastrocnemius (+22 or +38%, respectively) of obese animals when compared to lean littermates. Basal synthesis rates of myofibrillar (+8%) and mitochondrial proteins (-1%) in quadriceps were not different between phenotypes, while manufacture of cytosolic proteins (+12%) was moderately elevated in obese cohorts. Western blot analyses revealed a robust activation of p70S6k (+178%) and a lower expression of the endogenous mTOR inhibitor DEPTOR (-28%) in obese rats, collectively suggesting that there is an obesity-induced increase in net protein turnover favoring degradation. Lastly, the protein synthetic response to exercise of mixed (-7%), myofibrillar (+6%), and cytosolic (+7%) quadriceps subfractions was blunted compared to the lean phenotype (+34, +40, and +17%, respectively), indicating a muscle- and subfraction-specific desensitization to the anabolic stimulus of exercise in obese animals.

Aberrant REDD1-mTORC1 responses to insulin in skeletal muscle from Type 2 diabetics

“…Consistent with the current finding that skeletal muscle from obese, T2D humans exhibit hyperactive mTORC1 signaling, our laboratory (18,19) and others (53,64,72,73) have reported similar findings in skeletal muscle from obese or insulin-resistant mouse models. Similarly, findings have been reported in adipocytes from lean vs. obese individuals (55).…”

Assessment of protein synthesis in highly aerobic canine species at the onset and during exercise training

“…However, in the absence of biopsies taken prior to initiation of the exercise training in the Labrador Retrievers, it is hard to make this determination. Although there is evidence from rodents that weight gain does not selectively change the synthesis rates of protein fractions (16), it is unknown whether this is true in dogs.…”

“…Longer periods of assessment are limited by the need to maintain a constant infusion of isotopes, thus restricting freeliving conditions. To address these limitations, we (4,5,13,14,19,22) and others (2,6,16,26) have employed stable isotope techniques that use deuterium oxide ( 2 H 2 O). By providing 2 H 2 O in the drinking water of humans (19,22) or rodents (4,5,13,14), we have assessed cumulative protein synthesis over the period of weeks, rather than hours.…”

Impaired exercise-induced mitochondrial biogenesis in the obese Zucker rat, despite PGC-1α induction, is due to compromised mitochondrial translation elongation

“…This is similar to a previous report by Holloway et al (13), who showed in lean and obese women that PGC-1␣ was uncoupled from fatty acid oxidation in obesity. Considering this finding and given our previous reports indicating most anabolic processes to be upregulated in obese animals (25,26) regardless of exercise, we elected to focus on specific anabolic factors associated with the mitochondrial genome as possible culprits for the lack of mitochondrial biogenesis in these animals. Therefore, we amended our hypothesis that exercise would induce transcription and translation of the mitochondrial genome but that said induction would be impaired in the obese/insulin resistant animal.…”