Summary Calorie restriction, without malnutrition, has been shown to increase lifespan and is associated with a shift away from glycolysis toward beta-oxidation. The objective of this study was to mimic this metabolic shift using low-carbohydrate diets and to determine the influence of these diets on longevity and healthspan in mice. C57BL/6 mice were assigned to a ketogenic, low-carbohydrate, or control diet at 12 months of age and were either allowed to live their natural lifespan or tested for physiological function after 1 or 14 months of dietary intervention. The ketogenic diet (KD) significantly increased median lifespan and survival compared to controls. In aged mice, only those consuming a KD displayed preservation of physiological function. The KD increased protein acetylation levels and regulated mTORC1 signaling in a tissue-dependent manner. This study demonstrates that a KD extends longevity and healthspan in mice.

Skeletal muscle atrophy is a severe consequence of ageing, neurological disorders and chronic disease. Identifying the intracellular signalling pathways controlling changes in skeletal muscle size and function is vital for the future development of potential therapeutic interventions. Striated activator of Rho signalling (STARS), an actin-binding protein, has been implicated in rodent cardiac hypertrophy; however its role in human skeletal muscle has not been determined. This study aimed to establish if STARS, as well as its downstream signalling targets, RhoA, myocardin-related transcription factors A and B (MRTF-A/B) and serum response factor (SRF), were increased and decreased respectively, in human quadriceps muscle biopsies taken after 8 weeks of both hypertrophy-stimulating resistance training and atrophy-stimulating de-training. The mRNA levels of the SRF target genes involved in muscle structure, function and growth, such as α-actin, myosin heavy chain IIa (MHCIIa) and insulin-like growth factor-1 (IGF-1), were also measured. Following resistance training, STARS, MRTF-A, MRTF-B, SRF, α-actin, MHCIIa and IGF-1 mRNA, as well as RhoA and nuclear SRF protein levels were all significantly increased by between 1.25-and 3.6-fold. Following the de-training period all measured targets, except for RhoA, which remained elevated, returned to base-line. Our results show that the STARS signalling pathway is responsive to changes in skeletal muscle loading and appears to play a role in both human skeletal muscle hypertrophy and atrophy.

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Hughes DC, Wallace MA, Baar K. Effects of aging, exercise, and disease on force transfer in skeletal muscle. Am J Physiol Endocrinol Metab 309: E1-E10, 2015. First published May 12, 2015; doi:10.1152/ajpendo.00095.2015.-The loss of muscle strength and increased injury rate in aging skeletal muscle has previously been attributed to loss of muscle protein (cross-sectional area) and/or decreased neural activation. However, it is becoming clear that force transfer within and between fibers plays a significant role in this process as well. Force transfer involves a secondary matrix of proteins that align and transmit the force produced by the thick and thin filaments along muscle fibers and out to the extracellular matrix. These specialized networks of cytoskeletal proteins aid in passing force through the muscle and also serve to protect individual fibers from injury. This review discusses the cytoskeleton proteins that have been identified as playing a role in muscle force transmission, both longitudinally and laterally, and where possible highlights how disease, aging, and exercise influence the expression and function of these proteins. force transmission; dystrophin-glycoprotein complex; injury; aging ON AVERAGE, HUMANS LOSE AROUND 45% of their muscle mass between their mid-20s and 80s (47,70,71). This loss in muscle mass in the absence of disease is known as sarcopenia (60). The decline in muscle mass is accompanied by, but cannot fully explain, a rapid loss in muscle strength (64). The loss in muscle strength has previously been investigated from the perspectives of loss of muscle protein mass (cross-sectional area) and decreased neural activation. A third possibility, impaired force transfer, has received the least attention in relation to aging, exercise, and disease (66,90,102). However, recent advances in our understanding of this process suggest that force transfer plays an important role in muscle strength and injury prevention, and this fact is the focus of this review. Force TransferOver 60 years ago, Andrew Huxley and his students used electron microscopy to show that during muscle contraction the I-band (containing the thin filament) shortened whereas the A-band (containing the thick filament) remained a constant length (39). Their famous "sliding theory of muscle contraction" provided an image of a muscle shortening end to end as the A-bands drew closer together. Implied in this model is that force is transferred in a longitudinal manner as a result of sarcomere shortening. However, a deeper consideration of this model requires that there be a secondary matrix of proteins that are not visible to the electron microscope, proteins that transmit the force produced by the thick and thin filaments along the muscle fiber to the tendons. These specialized networks of cytoskeletal proteins transmit force through the muscle to the tendon and also serve to protect individual fibers from injury.An important structure in these networks is the "costamere", which connects the sarcolemma with the contractile appar...

Non-technical summary Exercise improves the ability of skeletal muscle to metabolise fats and sugars. For these improvements to occur the muscle detects a signal caused by exercise, resulting in changes in genes and proteins that control metabolism. We show that endurance exercise increases the amount of a protein called striated muscle activator of Rho signalling (STARS) as well as several other proteins influenced by STARS. We also show that the amount of STARS can be increased by signals directed from proteins called peroxisome proliferator-activated receptor gamma co-activator 1-α (PGC-1α) and oestrogen-related receptor-α (ERRα). We also observed that when we reduce the amount of STARS in muscle cells, we block the ability of PGC-1α/ERRα to increase a gene called carnitine palmitoyltransferase-1β (CPT-1β), which is important for fat metabolism. Our study has shown that the STARS pathway is regulated by endurance exercise. STARS may also play a role in fat metabolism in muscle.Abstract The striated muscle activator of Rho signalling (STARS) is an actin-binding protein specifically expressed in cardiac, skeletal and smooth muscle. STARS has been suggested to provide an important link between the transduction of external stress signals to intracellular signalling pathways controlling genes involved in the maintenance of muscle function. The aims of this study were firstly, to establish if STARS, as well as members of its downstream signalling pathway, are upregulated following acute endurance cycling exercise; and secondly, to determine if STARS is a transcriptional target of peroxisome proliferator-activated receptor gamma co-activator 1-α (PGC-1α) and oestrogen-related receptor-α (ERRα). When measured 3 h post-exercise, STARS mRNA and protein levels as well as MRTF-A and serum response factor (SRF) nuclear protein content, were significantly increased by 140, 40, 40 and 40%, respectively. Known SRF target genes, carnitine palmitoyltransferase-1β (CPT-1β) and jun B proto-oncogene (JUNB), as well as the exercise-responsive genes PGC-1α mRNA and ERRα were increased by 2.3-, 1.8-, 4.5-and 2.7-fold, 3 h post-exercise. Infection of C2C12 myotubes with an adenovirus-expressing human PGC-1α resulted in a 3-fold increase in Stars mRNA, a response that was abolished following the suppression of endogenous ERRα. Over-expression of PGC-1α also increased Cpt-1β, Cox4 and Vegf mRNA by 6.2-, 2.0-and 2.0-fold, respectively. Suppression of endogenous STARS reduced basal Cpt-1β levels by 8.2-fold and inhibited the PGC-1α-induced increase in Cpt-1β mRNA. Our results show for the first time that the STARS signalling pathway is upregulated in response to acute endurance exercise. Additionally, we show in C2C12 myotubes that the STARS gene is a PGC-1α/ERRα transcriptional target. Furthermore, our results suggest a novel role of STARS in the co-ordination of PGC-1α-induced upregulation of the fat oxidative gene, CPT-1β.