Translational insights into the phenotype of sarcopenic obesity

FIRST PART: ANIMAL STUDY: Impact of protein intake and high-fat diet on muscle protein synthesis, ectopic lipid infiltration, energy balance and metabolic flexibility in relation to aging in rats Background Ectopic lipid deposition impairs muscle anabolic response especially during aging. We hypothesized that the anabolic efficiency of dietary protein in skeletal muscle might be affected within the context of high-fat diet. Aims The objectives of the study were to investigate muscle protein synthesis, intramuscular lipid deposition, energy balance, and metabolic flexibility in response to two levels of protein intake combined to two levels of fat intake. Methods Two groups of fifty-eight adult and forty-one old male Wistar rats were randomly divided into four groups: isocaloric standard diet (12% protein, 14% lipid, as STD12); isocaloric standard (high-protein) diet (25% protein, 14% lipid, STD25); hypercaloric high-fat (normal-protein) diet (12% protein, 45% lipid, HFD12); and hypercaloric high-fat (high-protein) diet (25% protein, 45% lipid, HFD25). The nutritional intervention lasted 10 weeks. The fractional synthesis (FSR) and absolute synthesis rates (ASR) of mixed muscle proteins were calculated using isotopically labelled C13-valine incorporation in tibialis anterior (TA). Muscle lipid content was assessed using a chromatography-based method. Protein efficiency ratio (PER) was calculated as PER = {100*[weight gain (g)/protein ingested (g)]}. Respiratory exchanges were assessed by indirect calorimetry, and respiratory quotient (RQ) was calculated. Metabolic flexibility and energy homeostasis were evaluated by the analysis of 24h-RQ using the relative cumulative frequency methodology. Results Rats in the high-fat diet groups self-limited their food intake, so that energy intake was not different among the groups. Regardless of dietary intervention, TA muscle weight was lower in old groups compared to their adult counterparts (all p values < 0.01). FSR was lower in old rats fed the HFD25 compared to the old STD12 group (diet effect : p=0.02), whereas FSR in old groups was higher than adult groups (age effect, all p values < 0.05). When considering the ASR, no differences emerged between groups except for a tendency towards higher ASR values in the old HFD12 group than the STD25 group (diet effect: p=0.09). Only old rats in the HFD12 group exhibited increased intramuscular triacylglycerols in TA (age effect : p=0.02 ; diet effect : HFD12 vs. STD 12: 2.04±1.74 vs. 0.83±0.49ug/g, p=0.02). PER was lower in the HFD25 group than the HFD12 group, regardless of age (old rats: 25.5 ± 6.2 vs. 57.4 ± 20.1, adult rats: 30.7 ± 15.9 vs. 78.84 ± 20.9, diet effect, p<0.05). In both adult and old rats, PER was higher in the HFD12 groups than the STD12 and STD25 groups (diet effect, p<0.05). Old rats in the HFD25 group exhibited lower RQ values than the HFD12 group, indicating that they relied more markedly on lipids as substrate for oxidation (RQ: 0.83 ± 0.04 vs. 0.87 ± 0.01, diet effect, p<0.05). The comparison between RQ and FQ indicated that, save in the HFD25 groups, RQ was higher than FQ, suggesting energy storage. Conclusion Aging is characterized by a reduced muscle weight despite an increased FSR, suggesting specific alterations in the nutritional regulation of muscle protein turnover. In isocaloric conditions, higher protein intake modulates muscle lipid infiltration, but does not improve age-related anabolic resistance in old rats fed a high-fat diet. SECOND PART: CLINICAL STUDY: The decline in muscle strength and muscle quality in relation to metabolic derangements in adult women with obesity Background & Aims: Sarcopenic obesity is a clinical syndrome described especially in the elderly in which excess fat and reduced muscularity coexist. The metabolic and functional characteristics related to sarcopenic obesity have not been thoroughly investigated in the early stages of the aging process. The aim of the present study was to investigate the phenotype of sarcopenic obesity- lean body mass, muscle strength and muscle quality in women with and without the Metabolic Syndrome (MetS), and its relationship with the features of myosteatosis. Methods: Study participants were enrolled at the Sapienza University, Rome, Italy. Body composition was assessed by DXA. The Handgrip strength test (HGST) was performed. HGST was normalized to arm lean mass to indicate muscle quality; intermuscular adipose tissue (IMAT) and intramyocellular lipid content (IMCL) were measured by magnetic resonance imaging and spectroscopy, as indicators of myosteatosis. Different indices of sarcopenia were calculated, based on appendicular lean mass (ALM, kg) divided by height squared, or weight, or BMI. The NCEP-ATPIII criteria were used to diagnose the MetS. HOMA-IR was calculated. The physical activity level (PAL) was assessed through the IPAQ questionnaire. Results: 54 women (age: 48±14 years, BMI: 37.9±5.4 kg/m2 ) were included. 54% had the MetS (metabolically unhealthy). HGST/arm lean mass was lower in metabolically unhealthy women than women without the MetS (6.3±1.8 vs. 7.8±1.6, p=0.03). No differences emerged in terms of absolute ALM (kg) or other indices of sarcopenia (ALM/h2 , ALM/weight, or ALM/BMI) between metabolically healthy vs. unhealthy women (p>0.05). Muscle quality (HGST/arm lean mass) was negatively associated with HOMA-IR (p=0.02), after adjustment for age, body fat, hs-CRP levels, and PAL. IMAT, but not IMCL, was significantly higher in obese women with the MetS compared to women without the MetS (p>0.05). No association emerged between HGST/arm lean mass and IMAT or IMCL when HOMA-IR was included in the models. Conclusion: Insulin resistance, and not myosteatosis per se, may play a role in the decline of muscle strength, leading to the phenotype of dynapenic obesity. Dynapenia may precede the decline of lean body mass in metabolically unhealthy obese women.