A transient increase in local pro-inflammatory cytokine expression following skeletal muscle injury mediates the repair and regeneration of damaged myofibers through myogenesis. Regenerative capacity is diminished and muscle wasting occurs, however, when intramuscular inflammatory signaling is exceedingly high or persists chronically. An excessive and persistent inflammatory response to muscle injury may therefore impair recovery by limiting the repair of damaged tissue and triggering muscle atrophy. The concentration-dependent activation of different downstream signaling pathways by several pro-inflammatory cytokines in cell and animal models support these opposing roles of post-injury inflammation. Understanding these molecular pathways is essential in developing therapeutic strategies to attenuate excessive inflammation and accelerate functional recovery and muscle mass accretion following muscle damage. This is especially relevant given the observation that basal levels of intramuscular inflammation and the inflammatory response to muscle damage are not uniform across all populations, suggesting certain individuals may be more susceptible to an excessive inflammatory response to injury that limits recovery. This narrative review explores the opposing roles of intramuscular inflammation in muscle regeneration and muscle protein turnover. Factors contributing to an exceedingly high inflammatory response to damage and age-related impairments in regenerative capacity are also considered.

Background & aims: Consuming 0.10e0.14 g essential amino acids (EAA)/kg/dose (0.25e0.30 g protein/ kg/dose) maximally stimulates muscle protein synthesis (MPS) during energy balance. Whether consuming EAA beyond that amount enhances MPS and whole-body anabolism following energy deficit is unknown. The aims of this study were to determine the effects of standard and high EAA ingestion on mixed MPS and whole-body protein turnover following energy deficit. Design: Nineteen males (mean ± SD; 23 ± 5 y; 25.4 ± 2.7 kg/m 2 ) completed a randomized, double-blind crossover study consisting of two, 5-d energy deficits (À30 ± 4% of total energy requirements), separated by 14-d. Following each energy deficit, mixed MPS and whole-body protein synthesis (PS), breakdown (PB), and net balance (NET) were determined at rest and post-resistance exercise (RE) using primed, constant L-[ 2 H 5 ]-phenylalanine and L-[ 2 H 2 ]-tyrosine infusions. Beverages providing standard (0.1 g/kg, 7.87 ± 0.87 g) or high (0.3 g/kg, 23.5 ± 2.54 g) EAA were consumed post-RE. Circulating EAA were measured. Results: Postabsorptive mixed MPS (%/h) at rest was not different (P ¼ 0.67) between treatments. Independent of EAA, postprandial mixed MPS at rest (standard EAA, 0.055 ± 0.01; high EAA, 0.061 ± 0.02) and post-RE (standard EAA, 0.055 ± 0.01; high EAA, 0.065 ± 0.02) were greater than postabsorptive mixed MPS at rest (P ¼ 0.02 and P ¼ 0.01, respectively). Change in (D postabsorptive) whole-body (g/ 180 min) PS and PB was greater for high than standard EAA [mean treatment difference (95% CI), 3.4 (2.3, 4.4); P ¼ 0.001 and À15.6 (À17.8, À13.5); P ¼ 0.001, respectively]. NET was more positive for high than standard EAA [19.0 (17.3, 20.7); P ¼ 0.001]. EAA concentrations were greater in high than standard EAA (P ¼ 0.001). Conclusions: These data demonstrate that high compared to standard EAA ingestion enhances wholebody protein status during underfeeding. However, the effects of consuming high and standard EAA on mixed MPS are the same during energy deficit.

Context: Male military personnel conducting strenuous operations experience reduced testosterone, muscle mass, and performance. Pharmacological restoration of normal testosterone may attenuate performance decrements by mitigating muscle loss. Previously, administering testosterone enanthate (200 mg/week) during energy deficit prompted supraphysiological testosterone concentrations and lean mass gain without preventing isokinetic/isometric deterioration. Whether administering a practical dose of testosterone protects muscle and performance during strenuous operations is undetermined. Objective: Test the effects of a single dose of testosterone on body composition and military-relevant physical performance during a simulated operation. Methods: After a 7-day baseline phase (P1), 32 males (mean±SD; 77.1±12.3 kg, 26.5±4.4 years) received a single dose of either testosterone undecanoate (750 mg; TEST) or placebo (PLA) before a 20-day simulated military operation (P2), followed by a 23-day recovery (P3). Assessments included body composition and physical performance at the end of each phase and circulating endocrine biomarkers throughout the study. Results: Total and free testosterone concentrations in TEST were greater than PLA throughout most of P2 (p<0.05), but returned to P1 values during P3. Fat-free mass (FFM) was maintained from P1 to P2 in TEST (mean±SE; 0.41±0.65 kg, p=0.53), but decreased in PLA (-1.85±0.69 kg, p=0.01) and recovered in P3. Regardless of treatment, total body mass and fat mass decreased from P1 to P2 (p<0.05), but did not fully recover by P3. Physical performance decreased during P2 (p<0.05) and recovered by P3, regardless of treatment. Conclusions: Administering testosterone undecanoate before a simulated military operation protected FFM but did not prevent decrements in physical performance.

Testosterone supplementation during energy deficit promotes whole-body lean mass accretion, but the mechanisms underlying that effect remain unclear. To elucidate those mechanisms, skeletal muscle molecular adaptations were assessed from muscle biopsies collected before (Resting), 1 h (Post) and 6 h (Recovery) after exercise and a mixed meal (40 g protein, 1 h post-exercise) following 14 days of weight maintenance (WM) and 28 days of an exercise- and diet-induced 55% energy deficit (ED) in 50 physically active, non-obese men treated with 200 mg testosterone enanthate/week (TEST) or placebo (PLA) during the ED. Participants (n=10/group) exhibiting substantial increases (TEST) in leg lean mass and total testosterone were compared to those exhibiting decreases in both of these measures (PLA). Resting androgen receptor (AR) protein content was higher and fibroblast growth factor-inducible 14 (Fn14), IL-6 receptor (IL-6R), and muscle ring-finger protein-1 (MuRF1) gene expression were lower in TEST versus PLA during ED relative to WM (P < 0.05). Changes in inflammatory, myogenic, and proteolytic gene expression did not differ between groups after exercise and recovery feeding. Mechanistic target of rapamycin (mTOR) signaling (i.e., translational efficiency) was also similar between groups at rest and after exercise and the mixed meal. Muscle total RNA content (i.e., translational capacity) increased more during ED in TEST than PLA (P < 0.05). These findings indicate that attenuated proteolysis at rest, possibly downstream of AR, Fn14, and IL-6R signaling, and increased translational capacity, not efficiency, may drive lean mass accretion with testosterone administration during energy deficit.

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Muscle atrophy and weakness occur as a consequence of disuse after musculoskeletal injury (MSI). The slow recovery and persistence of these deficits even after physical rehabilitation efforts indicate that interventions designed to attenuate muscle atrophy and protect muscle function are necessary to accelerate and optimize recovery from MSI. Evidence suggests that manipulating protein intake via dietary protein or free amino acid–based supplementation diminishes muscle atrophy and/or preserves muscle function in experimental models of disuse (i.e., immobilization and bed rest in healthy populations). However, this concept has rarely been considered in the context of disuse following MSI, which often occurs with some muscle activation during postinjury physical rehabilitation. Given that exercise sensitizes skeletal muscle to the anabolic effect of protein ingestion, early rehabilitation may act synergistically with dietary protein to protect muscle mass and function during postinjury disuse conditions. This narrative review explores mechanisms of skeletal muscle disuse atrophy and recent advances delineating the role of protein intake as a potential countermeasure. The possible synergistic effect of protein-based interventions and postinjury rehabilitation in attenuating muscle atrophy and weakness following MSI is also considered.

Interest in low-carbohydrate, high-fat (LCHF) diets has increased over recent decades given the theorized benefit of associated intramuscular adaptations and shifts in fuel utilization on endurance exercise performance. Consuming a LCHF diet during exercise training increases the availability of fat (i.e., intramuscular triglyceride stores; plasma free fatty acids) and decreases muscle glycogen stores. These changes in substrate availability increase reliance on fat oxidation for energy production while simultaneously decreasing reliance on carbohydrate oxidation for fuel during submaximal exercise. LCHF diet-mediated changes in substrate oxidation remain even after endogenous or exogenous carbohydrate availability is increased, suggesting that the adaptive response driving changes in fat and carbohydrate oxidation lies within the muscle and persists even when the macronutrient content of the diet is altered. This narrative review explores the intramuscular adaptations underlying increases in fat oxidation and decreases in carbohydrate oxidation with LCHF feeding. The possible effects of LCHF diets on protein metabolism and post-exercise muscle remodeling are also considered.