The Yucatan minipig model: A new preclinical model of malnutrition in obese patients with acute or chronic diseases.

BACKGROUND & AIMS: Malnutrition can develop in patients with obesity suffering from acute or chronic illness or after obesity surgery, promoting sarcopenic obesity. A better understanding of this pathophysiology and the development of new therapeutics for chronic diseases, that are often complicated with malnutrition and obesity, justify the development of new animal experimental models close to the human physiology. This study aims to characterize the effects of obesity and underfeeding on Yucatan obese minipigs, assessing its validity as a preclinical model for obesity-related malnutrition. METHODS: Sixteen 30-month-old Yucatan minipigs were divided into two groups for 8 weeks: a standard diet group (ST, n = 5) and an obesogenic diet group (OB, n = 11). After 8 weeks, the OB group was further divided into two sub-groups: a standard diet group (OB-ST, n = 5) and a low-calorie/low-protein diet group (OB-LC/LP, n = 6) for 8 weeks. Body composition by CT-Scan and blood parameters were monitored, and trapezius muscle biopsies were collected to analyse signaling pathways involved in protein turnover and energy metabolism. RESULTS: At W8, OB-ST animals exhibited significantly higher body weight (+37.7%, p = 0.03), muscle mass (+24.9%, p = 0.02), and visceral fat (+192.0%, p = 0.03) compared to ST. Trapezius cross sectional area (CSA) normalized to body weight was lower in OB-ST animals (-15.02%, p = 0.017). At W16, no significant changes were observed in protein turnover markers, although REDD1 increased in OB-ST (96.4%, p = 0.02). After 8 weeks of low-caloric/low protein diet, OB-LC/LP showed decreased body weight (-9.8%, p = 0.03), muscle mass (-6.5%, p = 0.03), and visceral fat (-41.5%, p = 0.03) compared to OB-ST animals. Trapezius fiber CSA significantly decreased in OB-LC/LP (-36.1%, p < 0.0001) and normalized to body weight (-25.4%, p < 0.0001), combined to higher ubiquitinated protein content (+38.3%, p = 0.02). CONCLUSION: Our data support that the Yucatan minipig model mimics nutritional and skeletal muscle phenotypes observed in obese patients, with or without protein-energy malnutrition. It also reproduces muscle atrophy observed in chronic diseases or post-obesity surgery, making it a promising preclinical model for obesity-related malnutrition.

The Yucatan minipig model: A new preclinical model of malnutrition induced by a low-calorie/low-protein diet.

BACKGROUND & AIMS: Severe malnutrition exposes patients to adverse outcomes and a higher mortality risk. The Yucatan minipig, closer to human physiology than murine models could be a pertinent and innovative experimental model for studying the physiopathology and consequences of severe malnutrition. The present study aimed to determine whether a low calorie/low protein diet (LC/LP) can reproduce marasmus malnutrition in minipigs, and to characterize body composition, gut microbiota, malnutrition-related blood parameters, and histological and molecular skeletal muscle patterns. METHODS: Eleven Yucatan minipigs were subjected to two different diets: a standard control diet (ST) (n = 5) and a LC/LP diet (n = 6). LC/LP animals daily received 50% of an isocaloric low-protein diet (10.37 MJ/kg, 8.6% protein). Body composition was measured by computed tomography (CT-scan) before (T0) and after 8 weeks of diet (T8). Trapezius and biceps femoris muscles were sampled at the end of protocol to perform histological and molecular analyses. Gut microbiota composition were was also analyzed at T0 and T8 in fecal samples. RESULTS: Eight weeks of LC/LP diet significantly reduced body weight (-12.3 ± 9.5%, P = 0.03) and gut microbiota richness (i.e. number of observed species) (-10.4 ± 8.3%, P = 0.014) compared to baseline. After 8 weeks, LC/LP animals exhibited a significant reduction of retroperitoneal fat and skeletal muscle surface areas (P = 0.03 and P = 0.047, respectively), whereas these parameters remained unchanged in ST animals. These reductions were associated with lower muscle fiber cross-sectional area (CSA) in trapezius (P < 0.001) and biceps femoris (P = 0.003) in LC/LP animals compared to ST. LC/LP diet promoted an increase of AMP kinase phosphorylation in trapezius and biceps femoris (P = 0.05), but did not affect cytochrome c and COX IV protein content, markers of mitochondrial content. Gene and proteins involved in ubiquitin-proteasome system and apoptosis remained unchanged after 8 weeks of LC/LP diet both in trapezius and biceps femoris. CONCLUSION: All these findings support that this experimental minipig model of severe malnutrition is valid to mimic pathophysiological changes occurring in human protein-energy marasmus malnutrition and muscle atrophy associated with malnutrition, as observed in patients with secondary sarcopenia.