Synergistic effects of MFG-E8 and whey protein on mitigating d-galactose-induced sarcopenia through PI3K/AKT/PGC-1α and MAPK/ERK signaling pathways.

Milk fat globule epidermal growth factor 8 (MFG-E8) and whey protein have emerged as promising bionutrient supplements for enhancing skeletal muscle mass and function. In the present study, aging-related sarcopenia rat model was employed to elucidate the effects of the combined administration of MFG-E8 and whey protein on the catabolism and anabolism of gastrocnemius protein. Combined intervention led to notable enhancements in the antioxidative stress status and mitochondrial biogenesis capacity of gastrocnemius muscle fibers in the aging rats, concomitant with a significant inhibition of lipid accumulation. Moreover, the synergistic effect of MFG-E8 and whey protein was found to exert modulatory effects on key signaling pathways, including PI3K/Akt/PGC-1α pathway and MAPK/ERK signaling pathways in the gastrocnemius muscle of the aging rats. Specifically, this combined intervention was observed to promote mitochondrial biogenesis and regulate the expression of protein anabolism and catabolism-related regulators, thereby facilitating the alleviation of mitochondrial oxidative stress and enhancing biogenesis in gastrocnemius tissues. The findings of our study provide compelling evidence for the potential of MFG-E8 as a promising dietary supplement with antisarcopenic properties to ameliorate muscle protein metabolism disorders and mitigate mitochondrial-mediated myoblast apoptosis induced by oxidative stress.

Identification and antioxidative mechanism of novel mitochondria-targeted MFG-E8 polypeptides in virtual screening and in vitro study.

Milk fat globule-EGF factor VIII (MFG-E8) has been identified as an important source of bioactive peptides, which may exert a pivotal role in regulating biologic redox equilibrium. However, the composition of MFG-E8 polypeptides and their mechanisms on mitigating sarcopenia remain unknown. The aim of this study was to identify the composition of MFG-E8 polypeptides and its effects against oxidative stress in dexamethasone-induced L6 cell injury. Simulated digestion in vitro and liquid chromatography-tandem mass spectrometry were used in this investigation. A total of 95 peptides were identified during complete simulated digestion; among them, the contents of 21 peptides were analyzed, having been determined to exceed 1%. Molecular docking assay found that IDLG, KDPG, YYR, and YYK exhibited high binding affinity with keap1. MTT, dichlorodihydrofluorescein diacetate, mito- and lyso-tracker, and transmission electron microscope assay demonstrated that IDLG and KDPG can alleviate oxidative stress-injured L6 cell vitality, mitochondria activity, vacuolation, and function decrease, and increased autophagy, thereby improving mitochondrial homeostasis. From a molecular perspective, IDLG and KDPG can decrease the expression of keap1 and increase the expression of Nrf2, HO-1, and PGC-1α. Therefore, MFG-E8-derived IDLG and KDPG could be potential polypeptides countering oxidative stress in the treatment of sarcopenia, via the keap1/Nrf2/HO-1 signaling pathway.

Ultrasonographic monitoring of feline epaxial muscle height as part of an annual wellness examination to assess for the development of sarcopenia.

OBJECTIVES: The aim of this study was to determine if epaxial muscle height (EMH) could be reliably incorporated into annual routine wellness screenings, and also determine its relationship to age, body condition score (BCS), subjective muscle assessment (SMA), breed and sex in mature cats. METHODS: EMH was determined independently by three observers from ultrasonographic examinations - collected by an additional trained individual - of cats enrolled at the Feline Healthy Ageing Clinic, University of Liverpool, UK. Age, body weight, BCS and SMA data were also collected. RESULTS: A total of 92 cats were included, 35 of which had repeat ultrasonographic examinations 12 months apart. Enrolled cats were a median age of 8 years and 9 months at the time of the first measurement. Variation in the quality of ultrasonographic images collected did not affect muscle depth measurements (P = 0.974). Further, there was good intra- and inter-observer repeatability for all observations (intraclass correlation range 0.97-0.99). There was a moderate positive association between EMH and body weight (r = 0.49, P <0.001) but no association with age (r = -0.05, P = 0.680). There were also positive associations in EMH among cats with different BCSs (P = 0.001) and SMAs (thoracic spine, P = 0.021; lumbar spine, P = 0.014), but breed (P = 0.429) and sex (P = 0.187) had no effect. Finally, there was no change in EMH measurements in the paired samples (P = 0.145) or correlation between percentage weight and EMH change over 12 months. CONCLUSIONS AND RELEVANCE: The accuracy of EMH measurement using ultrasonographic imaging is good, irrespective of observer experience and provided that the ultrasonographer has some training. This suggests that ultrasonographic measurement of EMH could have a major practical impact as a non-invasive determination of muscle mass in pet cat populations. Further research is required to assess longitudinal changes in muscle mass over time in senior pet cats.

Nutritional Concerns for Cancer, Cachexia, Frailty, and Sarcopenia in Canine and Feline Pets.

Cachexia and frailty can be described as independent entities yet are interrelated as constituents of malnutrition and the aging process. The unifying aspect is lean muscle loss, ultimately driven by inflammation and the adverse ramifications to pets with chronic, debilitating, or terminal disease states, including cancer. Modification to intake of dietary protein, fat, omega-3 fatty acids, and selected vitamins has shown benefit in management protocols as preventative and palliative care, but further investigation is imperative.

Progressive Degenerative Myopathy and Myosteatosis in ASNSD1-Deficient Mice.

Mice with an inactivating mutation in the gene encoding asparagine synthetase domain containing 1 (ASNSD1) develop a progressive degenerative myopathy that results in severe sarcopenia and myosteatosis. ASNSD1 is conserved across many species, and whole body gene expression surveys show maximal expression levels of ASNSD1 in skeletal muscle. However, potential functions of this protein have not been previously reported. Asnsd1-/- mice demonstrated severe muscle weakness, and their normalized body fat percentage on both normal chow and high fat diets was greater than 2 SD above the mean for 3651 chow-fed and 2463 high-fat-diet-fed knockout (KO) lines tested. Histologic lesions were essentially limited to the muscle and were characterized by a progressive degenerative myopathy with extensive transdifferentiation and replacement of muscle by well-differentiated adipose tissue. There was minimal inflammation, fibrosis, and muscle regeneration associated with this myopathy. In addition, the absence of any signs of lipotoxicity in Asnsd1-/- mice despite their extremely elevated body fat percentage and low muscle mass suggests a role for metabolic dysfunctions in the development of this phenotype. Asnsd1-/- mice provide the first insight into the function of this protein, and this mouse model could prove useful in elucidating fundamental metabolic interactions between skeletal muscle and adipose tissue.

Usefulness of muscle condition score and ultrasonographic measurements for assessment of muscle mass in cats with cachexia and sarcopenia.

OBJECTIVE: To compare muscle condition scores (MCSs) and muscle ultrasonographic measurements in cats with and without muscle loss and to evaluate repeatability and reproducibility of MCS assessment. ANIMALS: 40 cats of various ages, body condition scores (BCSs), and MCSs. PROCEDURES: A prospective cross-sectional study was conducted. Body weight, BCS, MCS, epaxial muscle height (EMH), vertebral epaxial muscle score (VEMS), and forelimb epaxial muscle score (FLEMS) were assessed in each cat. The MCS for each cat was assessed 3 separate times by each of 5 raters. RESULTS: The MCS was significantly correlated with EMH (r = 0.59), VEMS (r = 0.66), and FLEMS (r = 0.41). For MCS, the overall value of the κ coefficient for interrater agreement (reproducibility) was 0.43 and the overall value of the κ coefficient for intrarater agreement (repeatability) ranged from 0.49 to 0.76. CONCLUSIONS AND CLINICAL RELEVANCE: Ultrasonographic measurements of muscle may be useful for assessing muscle loss in individual cats over time. However, for the cats of this study, no advantage was observed for assessment of VEMS or FLEMS over EMH. Substantial repeatability and moderate reproducibility were shown when MCS was used for assessment of muscle mass in cats. Prospective ultrasonographic studies are warranted to evaluate the usefulness of MCS and EMH assessment for evaluation of changes in muscle mass of cats over time.

Age-Related Changes in Skeletal Muscle of Cattle.

Sarcopenia, the age-related loss of muscle mass and strength, is a multifactorial condition that represents a major healthcare concern for the elderly population. Although its morphologic features have been extensively studied in humans, animal models, and domestic and wild animals, only a few reports about spontaneous sarcopenia exist in other long-lived animals. In this work, muscle samples from 60 healthy Podolica-breed old cows (aged 15-23 years) were examined and compared with muscle samples from 10 young cows (3-6 years old). Frozen sections were studied through standard histologic and histoenzymatic procedures, as well as by immunohistochemistry, immunofluorescence, and Western blot analysis. The most prominent age-related myopathic features seen in the studied material included angular fiber atrophy (90% of cases), mitochondrial alterations (ragged red fibers, 70%; COX-negative fibers, 60%), presence of vacuolated fibers (75%), lymphocytic (predominantly CD8+) inflammation (40%), and type II selective fiber atrophy (40%). Immunohistochemistry revealed increased expression of major histocompatibility complex I in 36 cases (60%) and sarcoplasmic accumulations of ß-amyloid precursor protein-positive material in 18 cases (30%). In aged cows, muscle atrophy was associated with accumulation of myostatin. Western blot analysis indicated increased amount of both proteins-myostatin and ß-amyloid precursor protein-in muscles of aged animals compared with controls. These findings confirm the presence of age-related morphologic changes in cows similar to human sarcopenia and underline the possible role of amyloid deposition and subsequent inflammation in muscle senescence.

Assessment of methods of evaluating sarcopenia in old dogs.

OBJECTIVE: To evaluate clinically applicable methods of assessing lean body mass in dogs and compare muscle mass and inflammatory markers in healthy young and old dogs. ANIMALS: 9 healthy young (1 to 5 years old) and 10 old (> 8 years old) Labrador Retrievers with a body condition score of 5 to 6 of 9. PROCEDURES: Radiography of the thoracolumbar region was performed for measurement of epaxial muscle height at the level of T13-L1. Computed tomographic images were obtained for the measurement of the epaxial and temporal muscles. Ultrasonography also was performed for regional muscle measurements at these same sites and the quadriceps muscle. Serum C-reactive protein, insulin-like growth factor-1, and tumor necrosis factor-α concentrations also were measured, and dogs' activity for 14 days was assessed with an activity monitor. RESULTS: Mean epaxial muscle area measured by ultrasonography was significantly lower in the old group, compared with the young group, whereas epaxial muscle area measured by CT was only significantly lower in the old group after normalization for vertebral height. Neither temporal and quadriceps muscle measurements nor serum C-reactive protein or insulin-like growth factor-1 concentrations were significantly different between age groups. Tumor necrosis factor-α concentrations were undetectable in all dogs. CONCLUSIONS AND CLINICAL RELEVANCE: This study documented reduced epaxial muscle area in healthy old Labrador Retrievers, consistent with the syndrome of sarcopenia. Ultrasonography and CT were feasible methods of measuring epaxial muscle area, but much additional research is required to assess this method. A better understanding of underlying mechanisms of sarcopenia as well as methods for slowing progression is needed.

Cachexia and sarcopenia: emerging syndromes of importance in dogs and cats.

Cachexia is the loss of lean body mass (LBM) that affects a large proportion of dogs and cats with congestive heart failure (CHF), chronic kidney disease (CKD), cancer, and a variety of other chronic diseases. Sarcopenia, the loss of LBM that occurs with aging, is a related syndrome, although sarcopenia occurs in the absence of disease. As many of the diseases associated with muscle loss are more common in aging, cachexia and sarcopenia often are concurrent problems. Both cachexia and sarcopenia have important clinical implications because they are associated with increased morbidity and mortality. The pathophysiology of these 2 syndromes is complex and multifactorial, but recent studies have provided new information that has helped to clarify mechanisms and identify potential new targets for treatment. Newly identified mechanisms and pathways that mediate cachexia appear to act by increasing energy requirements, decreasing energy intake, impairing nutrient absorption, and causing metabolic alterations. Whereas cachexia and sarcopenia are important areas of research for drug development in people, they are only beginning to be recognized in veterinary medicine. Greater awareness and earlier diagnosis will help provide practical approaches to managing body weight and lean tissue in dogs and cats, as well as more directed targets for treatment.