Sarcopenia is defined as the combined loss of skeletal muscle strength, function, and/or mass with aging. This degenerative loss of muscle mass is associated with poor quality of life and early mortality humans. The loss of muscle mass occurs due to acute changes in daily muscle net protein balance (NPB). It is generally believed a poor NPB occurs due to reduced muscle protein synthetic responses to exercise, dietary amino acid availability, or an insensitivity of insulin to suppress breakdown. Hence, aging muscles appear to be resistant to the anabolic action of exercise and protein (amino acids or hormonal) when compared to their younger counterparts. The mechanisms that underpin anabolic resistance to anabolic stimuli (protein and resistance exercise) are multifactorial and may be partly driven by poor lifestyle choices (increased sedentary time and reduced dietary protein intake) as well as an inherent dysregulated mechanism in old muscles irrespective of the environmental stimuli. The insulin like growth factor 1 (IGF-1), Akt /Protein Kinase B and mechanistic target of rapamycin (mTOR) pathway is the primary driver between mechanical contraction and protein synthesis and may be a site of dysregulation between old and younger people. Therefore, our review aims to describe and summarize the differences seen in older muscle in this pathway in response to resistance exercise (RE) and describe approaches that researchers have sought out to maximize the response in muscle. Furthermore, this review will present the hypothesis that inositol hexakisphosphate kinase 1 (IP6K1) may be implicated in IGF-1 signaling and thus sarcopenia, based on recent evidence that IGF-1 and insulin share some intracellular bound signaling events and that IP6K1 has been implicated in skeletal muscle insulin resistance.

Background: We have recently shown that a novel signalling kinase, inositol hexakisphosphate kinase 1 (IP6K1), is implicated in whole-body insulin resistance via its inhibitory action on Akt. Insulin and insulin like growth factor 1 (IGF-1) share many intracellular processes with both known to play a key role in glucose and protein metabolism in skeletal muscle. Aims: We aimed to compare IGF/IP6K1/Akt signalling and the plasma proteomic signature in individuals with a range of BMIs after ingestion of lean meat. Methods: Ten lean [Body mass index (BMI) (in kg/m 2): 22.7 ± 0.4; Homeostatic model assessment of insulin resistance (HOMA IR): 1.36 ± 0.17], 10 overweight (BMI: 27.1 ± 0.5; HOMA IR : 1.25 ± 0.11), and 10 obese (BMI: 35.9 ± 1.3; HOMA IR : 5.82 ± 0.81) adults received primed continuous L-[ring-13 C 6 ]phenylalanine infusions. Blood and muscle biopsy samples were collected at 0 min (post-absorptive), 120 min and 300 min relative to the ingestion of 170 g pork loin (36 g protein and 5 g fat) to examine skeletal muscle protein signalling, plasma proteomic signatures, and whole-body phenylalanine disappearance rates (R d). Results: Phenylalanine R d was not different in obese compared to lean individuals at all time points and was not responsive to a pork ingestion (basal, P = 0.056; 120 & 300 min, P N 0.05). IP6K1 was elevated in obese individuals at 120 min post-prandial vs basal (P b 0.05). There were no acute differences plasma proteomic profiles between groups in the post-prandial state (P N 0.05). Conclusions: These data demonstrate, for the first time that muscle IP6K1 protein content is elevated after lean meat ingestion in obese adults, suggesting that IP6K1 may be contributing to the dysregulation of nutrient uptake in skeletal muscle. In addition, proteomic analysis showed no differences in proteomic signatures between obese, overweight or lean individuals.

The progression from pre-diabetes to overt type 2 diabetes is largely attributed to β-cell dysfunction and reduced insulin responsiveness. Exercise improves β-cell function in type 2 diabetics, however in pre-diabetic populations there is no data to support a similar response to acute high intensity exercise. Nine individuals diagnosed with prediabetes [HbA1c; 6.1 (0.2)%)] underwent a resting control, a continuous exercise and a high-intensity exercise trial. A labeled ([6,6 2 H 2 ] glucose) intravenous glucose tolerance test (IVGTT) was administered immediately after each trial to calculate β-cell function, 1 st [acute (AIR g )] and 2 nd phase insulin response to intravenous glucose and disposition index (DI). Data modelling indicated AIR g (P = 0.68) and 2 nd phase insulin responsiveness (P = 0.294) were not different between trials. Additionally, insulin response in relation to insulin action (DI) was not statistically different between trials (P = 0.394). In conclusion, acute high intensity exercise does not improve DI and β-cell function in individuals with prediabetes.

BackgroundInositol hexakisphosphate Kinase 1 (IP6K1) has been identified as a key signalling enzyme that inhibits Akt activity in hepatic cell lines and diabetic rodent models (Chakraborty et al., 2010; 2012; Goshal et al., 2016). Given both glucose transport and protein synthesis require Akt activation, we investigate if IP6K1 altered the IGF ‐ Akt – mTOR signalling cascade.MethodsC2C12 mouse skeletal myoblast cells were cultured in 12mL growth media (500mL DMEM, 10% FBS, 1% anti ‐ anti, 1% penicillin ‐ streptomycin) under standard conditions, changing media every 24 – 48 hours. Once 80% confluence was reached myoblasts were incubated in 12mL differentiation media (500mL DMEM, 2% donor equine serum, 1% anti ‐anti, 1% penicillin ‐ streptomycin) for 96 hours, changing media every 24 – 48 hours, to form mature myotubes. Myotubes were treated with IGF −1 (10ng/ml) +/− N2‐(m‐(trifluoromethy)lbenzyl) N6‐(p‐nitrobenzyl)purine (TNP; 10μm) for 24 hours before being lysed (1X cell lysis buffer supplemented with protease and phosphatase inhibitor cocktail) and total protein content determined using Lowry method. Western blot analysis was used to quantify t‐Akt, p‐Akt308, p‐Akt473, t‐mTOR, p‐mTOR2448 and IP6K1.ResultsA significant condition x IP6K1 effect was noted (P < 0.05) between IGF – 1 treatment and control in C2C12 myotubes, whilst IGF – 1 + TNP decreased IP6K1 content compared to IGF – 1 alone (P < 0.05). Significant differences were observed between IGF – 1 + TNP and control in p‐Akt308 and p‐Akt473 (P < 0.05), however no significant differences were observed between IGF – 1 + TNP and control in p/Akt308, p/Akt473 and p/mTOR2448 (P > 0.05).ConclusionsThis research is the first to characterize IP6K1 signalling in the IGF – 1, Akt – mTOR signalling cascade in C2C12 muscle cells. A reduction in IP6K1 did not increase p‐Akt or p‐mTOR activity.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.