Gait parameters that can be measured with simple instrumentation may hold promise for identifying individuals at risk of falling. Increased variability of gait is associated with increased risk of falling, but research on additional parameters indicates that local dynamic stability (LDS) of gait may also be a predictor of fall risk. The objective of the present study was to assess the association between gait variability, LDS of gait and fall history in a large sample of elderly subjects. Subjects were recruited and tested at a large national fair. One hundred and thirty four elderly, aged 50-75, who were able to walk without aids on a treadmill, agreed to participate. After subjects walked on a treadmill, LDS (higher values indicate more instability) and variability parameters were calculated from accelerometer signals (trunk worn). Fall history was obtained by self-report of falls in the past 12 months. Gait variability and short-term LDS were, individually and combined, positively associated with fall history. In conclusion, both increased gait variability and increased short-term LDS are possible risk factors for falling in the elderly.

The coactivator PGC-1α1 is activated by exercise training in skeletal muscle and promotes fatigue-resistance. In exercised muscle, PGC-1α1 enhances the expression of kynurenine aminotransferases (Kats), which convert kynurenine into kynurenic acid. This reduces kynurenine-associated neurotoxicity and generates glutamate as a byproduct. Here, we show that PGC-1α1 elevates aspartate and glutamate levels and increases the expression of glycolysis and malate-aspartate shuttle (MAS) genes. These interconnected processes improve energy utilization and transfer fuel-derived electrons to mitochondrial respiration. This PGC-1α1-dependent mechanism allows trained muscle to use kynurenine metabolism to increase the bioenergetic efficiency of glucose oxidation. Kat inhibition with carbidopa impairs aspartate biosynthesis, mitochondrial respiration, and reduces exercise performance and muscle force in mice. Our findings show that PGC-1α1 activates the MAS in skeletal muscle, supported by kynurenine catabolism, as part of the adaptations to endurance exercise. This crosstalk between kynurenine metabolism and the MAS may have important physiological and clinical implications.

Adequate skeletal muscle plasticity is an essential element for our well-being, and compromised muscle function can drastically affect quality of life, morbidity, and mortality. Surprisingly, however, skeletal muscle remains one of the most under-medicated organs. Interventions in muscle diseases are scarce, not only in neuromuscular dystrophies, but also in highly prevalent secondary wasting pathologies such as sarcopenia and cachexia. Even in other diseases that exhibit a well-established risk correlation of muscle dysfunction due to a sedentary lifestyle, such as type 2 diabetes or cardiovascular pathologies, current treatments are mostly targeted on non-muscle tissues. In recent years, a renewed focus on skeletal muscle has led to the discovery of various novel drug targets and the design of new pharmacological approaches. This review provides an overview of the current knowledge of the key mechanisms involved in muscle wasting conditions and novel pharmacological avenues that could ameliorate muscle diseases. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 59 is January 6, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is abundantly expressed in trained muscles and regulates muscle adaptation to endurance exercise. Inversely, mice lacking a functional PGC-1α allele in muscle exhibit reduced muscle functionality and increased inflammation. In isolated muscle cells, PGC-1α and the related PGC-1β counteract the induction of inflammation by reducing the activity of the nuclear factor κB (NFκB). We now tested the effects of these metabolic regulators on inflammatory reactions in muscle tissue of control and muscle-specific PGC-1α/-1β transgenic mice in vivo in the basal state as well as after an acute inflammatory insult. Surprisingly, we observed a PGC-1-dependent alteration of the cytokine profile characterized by an increase in anti-inflammatory factors and a strong suppression of the pro-inflammatory interleukin 12 (IL-12).In conclusion, the anti-inflammatory environment in muscle that is promoted by the PGC-1s might contribute to the beneficial effects of these coactivators on muscle function and provides a molecular link underlying the tight mutual regulation of metabolism and inflammation.

We determined the genotype and allelic frequency of several genetic polymorphisms (ACE I/D, GDF-8K153R [and also E164K, P198A and I225T] and AMPD1 C34T) that are candidates to influence sports performance in a group of 54 male professional soccer players. Their results were compared with those of elite endurance male athletes (52 runners) and 123 sedentary, healthy men (controls). We found statistical significance for the ACE ID (chi (2)((2))=8.176, P=0.017) and II genotypes (chi(2)((2))=16.137, P<0.001) with a higher and lower frequency of ID ( P=0.005) and II (P<0.001), respectively, in soccer players than in endurance runners. Statistical significance was also reached for AMPD1 (with a higher frequency of the CT genotype in soccer players than in runners [chi(2)((2))=7.538, P=0.006]) but not for GDF-8 K153R. Since the ACE II genotype is associated with improved potential for endurance performance but with decreased training gains in muscle mass and strength, these findings together with previous results support the notion that elite soccer players tend to have a power/strength oriented genotype.