Highlights d In DMD muscle, Ly6C pos macrophages produce latent TGF-b1 due to high LTBP4 synthesis d AMPK activation downregulates LTBP4 expression and TGF-b1 production by macrophages d Metformin treatment of DMD mice decreases fibrosis and improves muscle function d Fibroblast-derived enzymes activate latent TGF-b1, which acts on fibroblasts

We concluded that the voluntary torque gains obtained after EMS training could be attributed to both muscular and neural adaptations. Both changes selectively involved the monoarticular vastii muscles.

The aim of the present study was to define the chronic effects of neuromuscular electrical stimulation (NMES) on the neuromuscular properties of human skeletal muscle. Eight young healthy male subjects were subjected to 25 sessions of isometric NMES of the quadriceps muscle over an 8-wk period. Needle biopsies were taken from the vastus lateralis muscle before and after training. The training status, myosin heavy chain (MHC) isoform distribution, and global protein pattern, as assessed by proteomic analysis, widely varied among subjects at baseline and prompted the identification of two subgroups: an "active" (ACT) group, which performed regular exercise and had a slower MHC profile, and a sedentary (SED) group, which did not perform any exercise and had a faster MHC profile. Maximum voluntary force and neural activation significantly increased after NMES in both groups (+∼30% and +∼10%, respectively). Both type 1 and 2 fibers showed significant muscle hypertrophy. After NMES, both groups showed a significant shift from MHC-2X toward MHC-2A and MHC-1, i.e., a fast-to-slow transition. Proteomic maps showing ∼500 spots were obtained before and after training in both groups. Differentially expressed proteins were identified and grouped into functional categories. The most relevant changes regarded 1) myofibrillar proteins, whose changes were consistent with a fast-to-slow phenotype shift and with a strengthening of the cytoskeleton; 2) energy production systems, whose changes indicated a glycolytic-to-oxidative shift in the metabolic profile; and 3) antioxidant defense systems, whose changes indicated an enhancement of intracellular defenses against reactive oxygen species. The adaptations in the protein pattern of the ACT and SED groups were different but were, in both groups, typical of both resistance (i.e., strength gains and hypertrophy) and endurance (i.e., a fast-to-slow shift in MHC and metabolic profile) training. These training-induced adaptations can be ascribed to the peculiar motor unit recruitment pattern associated with NMES.

The study was conducted first, to determine the possibility of a dichotomy between circadian rhythm of maximal torque production of the knee extensors of the dominant and non-dominant legs, and second, to determine whether the possible dichotomy could be linked to a change in the downward drive of the central nervous system and/or to phenomena prevailing at the muscular level. The dominant leg was defined as the one with which subjects spontaneously kick a football. Tests were performed at 06:00, 10:00, 14:00, 18:00, and 22:00 h. To distinguish the neural and muscular mechanisms that influence muscle strength, the electromyographic and mechanical muscle responses associated with electrically evoked and/or voluntary contractions of the human quadriceps and semi-tendinosus muscles for each leg were recorded and compared. The main finding was an absence of interaction between time-of-day and dominance effects on the torque associated with maximal voluntary contraction (MVC) of both quadriceps. A significant time-of-day effect on MVC torque of the knee extensors was observed for the dominant and non-dominant legs when the data were collapsed, with highest values occurring at 18:00 h (p < 0.01). From cosinor analysis, a circadian rhythm was documented (p < 0.001) with the peak (acrophase) estimated at 18:18 +/- 00:12 h and amplitude (one-half the peak-to-trough variation) of 3.3 +/- 1.1%. Independent of the leg tested, peripheral mechanisms demonstrated a significant time-of-day effect (p < 0.05) on the peak-torque of the single and doublet stimulations, with maximal levels attained at 18:00 h. The central activation of the quadriceps muscle of each leg remained unchanged during the day. The present results confirmed previous observations that muscle torque changes in a predictable manner during the 24 h period, and that the changes are linked to modifications prevailing at the muscular, rather than the neural, level. The similar rhythmicity observed in this study between the dominant and non-dominant legs provides evidence that it is not essential to test both legs when simple motor tasks are investigated as a function of the time of day.

The aim of the study was to use combined longitudinal measurements of soleus (SOL) and gastrocnemii evoked V-wave and H-reflex responses to determine the site of adaptations within the central nervous system induced by 5 wk of neuromuscular electrical stimulation (NMES) training of the plantar flexor muscles. Nineteen healthy males subjects were divided into a neuromuscular electrostimulated group (n = 12) and a control group (n = 7). The training program consisted of 15 sessions of isometric NMES over a 5-wk period. All subjects were tested before and after the 5-wk period. SOL, lateral gastrocnemius (LG), and medial gastrocnemius (MG) maximal H-reflex and M-wave potentials were evoked at rest (i.e., H(max) and M(max), respectively) and during maximal voluntary contraction (MVC) (i.e., H(sup) and M(sup), respectively). During MVC, a supramaximal stimulus was delivered that allowed us to record the V-wave peak-to-peak amplitudes from all three muscles. The SOL, LG, and MG electromyographic (EMG) activity as well as muscle activation (twitch interpolation technique) were also quantified during MVC. After training, plantar flexor MVC increased significantly by 22% (P < 0.001). Torque gains were accompanied by an increase in muscle activation (+11%, P < 0.05), SOL, LG, and MG normalized EMG activity (+51, +54, and +60%, respectively, P < 0.05) and V/M(sup) ratios (+81, +76, and +97%, respectively, P < 0.05). H(max)/M(max) and H(sup)/M(sup) ratios for all three muscles were unchanged after training. In conclusion, the increase in voluntary torque after 5 wk of NMES training could be ascribed to an increased volitional drive from the supraspinal centers and/or adaptations occurring at the spinal level.

Body composition has gained increasing attention in oncology in recent years due to fact that sarcopenia has been revealed to be a strong prognostic indicator for survival across multiple stages and cancer types and a predictive factor for toxicity and surgery complications. Accumulating evidence over the last decade has unraveled the "pharmacology" of sarcopenia. Lean body mass may be more relevant to define drug dosing than the "classical" body surface area or flat-fixed dosing in patients with cancer. Since sarcopenia has a major impact on patient survival and quality of life, therapeutic interventions aiming at reducing muscle loss have been developed and are being prospectively evaluated in randomized controlled trials. It is now acknowledged that this supportive care dimension of oncological management is essential to ensure the success of any anticancer treatment. The field of sarcopenia and body composition in cancer is developing quickly, with (i) the newly identified concept of sarcopenic obesity defined as a specific pathophysiological entity, (ii) unsolved issues regarding the best evaluation modalities and cutoff for definition of sarcopenia on imaging, (iii) first results from clinical trials evaluating physical activity, and (iv) emerging body-compositiontailored drug administration schemes. In this context, we propose a comprehensive review providing a panoramic approach of the clinical, pharmacological and therapeutic implications of sarcopenia and body composition in oncology.

Authorship note: SM, GJ, and TG share first authorship. MP and RM share senior authorship. Conflict of interest: MP is on the Scientific Advisory Board of ResoTher Pharma AS, which is interested in the development of annexin A1-derived peptides for cardiovascular settings.

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