Human skeletal muscle disuse atrophy: effects on muscle protein synthesis, breakdown and insulin resistance- a qualitative review

The ever increasing burden of an ageing population and pandemic of metabolic syndrome worldwide demands further understanding of the modifiable risk factors in reducing disability and morbidity associated with these conditions. Disuse skeletal muscle atrophy (sometimes referred to as “simple” atrophy) and insulin resistance are ‘non-pathological’ events resulting from sedentary behaviour and periods of enforced immobilization e.g. due to fractures or elective orthopaedic surgery. Yet, the processes and drivers regulating disuse atrophy and insulin resistance and the associated molecular events remain unclear – especially in humans. The aim of this review is to present current knowledge of relationships between muscle protein turnover, insulin resistance and muscle atrophy during disuse, principally in humans. Immobilisation lowers fasted state muscle protein synthesis (MPS) and induces fed-state ‘anabolic resistance’. While a lack of dynamic measurements of muscle protein breakdown (MPB) precludes defining a definitive role for MPB in disuse atrophy, some proteolytic “marker” studies (e.g. MPB genes) suggest a potential early elevation. Immobilisation also induces muscle insulin resistance (IR). Moreover, the trajectory of muscle atrophy appears to be accelerated in persistent IR states (e.g. Type II diabetes), suggesting IR may contribute to muscle disuse atrophy under these conditions. Nonetheless, the role of differences in insulin sensitivity across distinct muscle groups and its effects on rates of atrophy remains unclear. Multifaceted time-course studies into the collective role of insulin resistance and muscle protein turnover in the setting of disuse muscle atrophy, in humans, are needed to facilitate the development of appropriate countermeasures and efficacious rehabilitation protocol

Pharmacological hypogonadism impairs molecular transducers of exercise-induced muscle growth in humans

Background: The relative role of skeletal muscle mechano-transduction in comparison with systemic hormones, such as testosterone (T), in regulating hypertrophic responses to exercise is contentious. We investigated the mechanistic effects of chemical endogenous T depletion adjuvant to 6weeks of resistance exercise training (RET) on muscle mass, function, myogenic regulatory factors, and muscle anabolic signalling in younger men. Methods: Non-hypogonadal men (n=16; 18–30years) were randomized in a double-blinded fashion to receive placebo (P, saline n=8) or the GnRH analogue, Goserelin [Zoladex (Z), 3.6mg, n=8], injections, before 6weeks of supervised whole-body RET. Participants underwent dual-energy X-ray absorptiometry (DXA), ultrasound of m. vastus lateralis (VL), and VL biopsies for assessment of cumulative muscle protein synthesis (MPS), myogenic gene expression, and anabolic signalling pathway responses. Results: Zoladex suppressed endogenous T to within the hypogonadal range and was well tolerated; suppression was associated with blunted fat free mass [Z: 55.4±2.8 to 55.8±3.1kg, P=0.61 vs. P: 55.9±1.7 to 57.4±1.7kg, P=0.006, effect size (ES)=0.31], composite strength (Z: 40±2.3% vs. P: 49.8±3.3%, P=0.03, ES=1.4), and muscle thickness (Z: 2.7±0.4 to 2.69±0.36cm, P>0.99 vs. P: 2.74±0.32 to 2.91±0.32cm, P0.99 vs. P: 1.9 fold, P0.99 vs. P: 4.7 fold, P=0.0005, ES=0.68; myogenin: Z: 1.3 fold, P>0.99 vs. P: 2.7 fold, P=0.002, ES=0.72), RNA/DNA (Z: 0.47±0.03 to 0.53±0.03, P=0.31 vs. P: 0.50±0.01 to 0.64±0.04, P=0.003, ES=0.72), and RNA/ASP (Z: 5.8±0.4 to 6.8±0.5, P>0.99 vs. P: 6.5±0.2 to 8.9±1.1, P=0.008, ES=0.63) ratios, as well as acute RET-induced phosphorylation of growth signalling proteins (e.g. AKTser473: Z: 2.74±0.6, P=0.2 vs. P: 5.5±1.1 fold change, P0.99 vs. P: 3.6±1 fold change, P=0.002, ES=0.53). Both MPS (Z: 1.45±0.11 to 1.50±0.06%·day−1, P=0.99 vs. P: 1.5±0.12 to 2.0±0.15%·day−1, P=0.01, ES=0.97) and (extrapolated) muscle protein breakdown (Z: 93.16±7.8 vs. P: 129.1±13.8g·day−1, P=0.04, ES=0.92) were reduced with hypogonadism result in lower net protein turnover (3.9±1.1 vs. 1.2±1.1g·day−1, P=0.04, ES=0.95). Conclusions: We conclude that endogenous T sufficiency has a central role in the up-regulation of molecular transducers of RET-induced muscle hypertrophy in humans that cannot be overcome by muscle mechano-transduction alone

Testosterone therapy induces molecular programming augmenting physiological adaptations to resistance exercise in older men

Background: The andropause is associated with declines in serum testosterone (T), loss of muscle mass (sarcopenia) and frailty. Two major interventions purported to offset sarcopenia are anabolic steroid therapies and resistance exercise training (RET). Nonetheless, the efficacy, and physiological and molecular impacts of T therapy adjuvant to short-term RET remain poorly defined.Methods: Eighteen non-hypogonadal healthy older men, 65-75 y, were assigned in a random double-blinded fashion to receive, bi-weekly, either placebo (P, saline, n=9) or T (Sustanon 250 mg, n=9) injections over 6-weeks whole-body RET (3-sets of 8-10 reps at 80% 1-RM). Subjects underwent dual-energy x-ray absorptiometry, ultrasound of vastus lateralis (VL) muscle architecture, and knee-extensor isometric muscle force tests; VL muscle biopsies were taken to quantify myogenic/anabolic gene expression, anabolic signalling, muscle protein synthesis (D2O) and breakdown (extrapolated).Results: T adjuvant to RET, augmented total fat free mass (FFM) (P=0.007), legs fat free mass (P=0.02), and appendicular FFM (P=0.001) gains, while decreasing total fat mass (P=0.02). Augmentations in VL muscle thickness, fascicle length, and quadriceps cross-section area with RET occured to a greater extent in T (P less than 0.05).Total strength (P=0.0009) and maximal voluntary contract (e.g. knee extension at 70°) (P=0.002) increased significantly more in the T group. Mechanistically, both muscle protein synthesis rates (T: 2.13±0.21%·day−1 vs. P: 1.34±0.13%·day−1, P=0.0009) and absolute breakdown rates (T: 140.2±15.8 vs. P: 90.2±11.7g·day-1, P=0.02) were elevated with T therapy, which led to higher net turnover and protein accretion in the T group (T: 8.3±1.4g·day-1 vs. P: 1.9±1.2 g·day-1, P=0.004). Increases in ribosomal biogenesis (RNA:DNA ratio); mRNA expression relating to T metabolism (Androgen Receptor: 1.4-fold; Srd5a1: 1.6-fold; AKR1C3: 2.1-fold; HSD17β3: 2-fold); IGF-1-signalling (IGF-1Ea (3.5-fold), IGF-1Ec (3-fold) and myogenic regulatory factors (MRF); as well the activity of anabolic signalling (e.g. mTOR, AKT, RPS6; P less than 0.05) were all upregulated with T therapy. Only T up-regulated mitochondrial citrate synthase activity (P=0.03) and transcription factor A (Tfam) (1.41±0.2-fold, P=0.0002), in addition to PGC1-α mRNA (1.19±0.21-fold, P=0.037).Conclusions: Administration of T adjuvant to RET enhanced skeletal muscle mass and performance, while upregulating myogenic gene programming, myocellular translational efficiency and capacity - collectively resulting in higher protein turnover, and net protein accretion. T coupled with RET is an effective short-term intervention to improve muscle mass/ function in older non-hypogonadal men