In skeletal muscle, resting cytosolic Ca2+ concentration ([Ca2+]cyto) homeostasis is exquisitely regulated by Ca2+ transport across the sarcolemmal, mitochondrial and sarcoplasmic reticulum (SR) membranes. Specifically, skeletal muscle contractile function is critically dependent on effective SR Ca2+ handling. However, more recent studies have revealed that mitochondria are essentially involved in [Ca2+]cyto homeostasis during and following muscle contractions. We recently provided substantial support for the mitochondria as a major site for Ca2+ sequestration in skeletal muscle during recovery from fatiguing tetanic contractions under in vivo conditions. This review provides an overview of the role of skeletal muscle mitochondria in [Ca2+]cyto regulation in vivo during and following muscle contractions.
Resident muscle stem cells are satellite cells that are responsible for the postnatal maintenance, growth, repair, and regeneration of skeletal muscle. In healthy adult muscle, satellite cells are mitotically quiescent, but are activated in response to stimulation such as muscle injury. Once activated, these cells then proliferate, with the majority of satellite cell progeny undergoing myogenic differentiation while the other cells return to a quiescent state and self-renew. Notch signaling is a highly conserved pathway that controls stem cell function in a variety of tissues including skeletal muscle. In this review, we discuss how Notch signaling acts as a regulator of the satellite cell pool and their fate decisions. Recent mouse genetic studies revealed that Notch signaling is essential for maintaining the satellite cell quiescent state in uninjured muscle, while it also allows for population expansion and promotes self-renewal when satellite cells are activated. Notably, diminished Notch activity in satellite cells is associated with muscle disorders such as age-related sarcopenia and muscular dystrophy. This review provides an overview of the multiple aspects of Notch signaling in muscle development and regeneration, and highlights recent studies that address its role in physiological and pathological conditions within muscle.
Recent evidence suggests that myostatin, a negative regulator of skeletal muscle growth, may play a key role in age-related muscle loss (sarcopenia). However, there is still no unified view on the changes in myostatin protein expression in skeletal muscle with aging. Therefore, this study was to investigate the age-associated changes in the protein expression of myostatin in both slow and fast rat skeletal muscles. Slow soleus and fast plantaris (PL), extensor digitorum longus (EDL), and tibiaris anterior (TA) muscles were dissected from male Wistar strain rats at different ages (7 weeks, and 1 and 2 years). A significant loss of muscle mass and myofibrillar protein content was observed between 1 year and 2 years of age in both slow soleus and fast PL, EDL, and TA muscles. Aging also resulted in a shift of myosin heavy chain expression toward slower isoforms in both slow and three fast skeletal muscles, although this isoform shift was already noted at 1 year of age. In contrast to these age-related changes, western blot analysis showed significantly higher expression of myostatin in fast PL, EDL, and TA, not in slow soleus, muscles in the 2-year-old group compared to the 7-week-old and 1-year-old groups. These results suggest that an age-associated increase in myostatin expression in fast skeletal muscle plays a key role in the onset and/or progression of sarcopenia, characterized by selective atrophy of fast type II muscle fibers.
The accumulation of advanced glycation end products (AGEs) in the body causes the pathogenesis of aging-related diseases by inhibiting the normal properties and functions of proteins and the modulation of cellular signal transduction. Glycation stress induced by AGEs accumulation has the potential to contribute to sarcopenia: age-related reductions in muscle mass, strength, and function. However, the molecular response to AGEs in skeletal muscle is not fully understood. Therefore, to understand changes in cellular signaling in response to AGEs, this study aimed to investigate the phosphorylation status of phosphoproteins in AGEs-treated skeletal muscle. Treatment of C2C12 skeletal muscle cells with glucose-induced AGEs (0.1 mg/mL) for 5 days suppressed myotube formation, and this was accompanied by Nε-carboxymethyl-lysine accumulation. Reverse phase protein array analysis revealed that treatment with AGEs (glyoxylic-, pyruvate-, glycolaldehyde-, and glucose-induced AGEs) increased phosphorylation at eight phosphorylation sites and decreased phosphorylation at 64 phosphorylation sites. The phosphorylation level of signal transducer and activator of transcription 3 (STAT3) Tyr705 was most enhanced, and that of extracellular signal-regulated kinase (ERK) Thr202/Tyr204 was most suppressed. Almost all phosphorylation sites related to insulin/insulin-like growth factor 1 signaling were downregulated by AGEs. Increased STAT3 Tyr705 phosphorylation and decreased ERK Thr202/Tyr204 phosphorylation were observed in the skeletal muscles of mice treated with a diet high in AGEs for 16 weeks. These findings suggest that AGE accumulation impairs cellular signal transduction pathways in skeletal muscle cells, and thereby has the potential to induce skeletal muscle loss.
Both exercise training and chronic caloric restriction contribute to brain health through enhanced expression of brain-derived neurotrophic factor (BDNF). This study investigated the synergistic effects between 12-week low-intensity exercise training and caloric restriction on hippocampal BDNF expression with redox status in rats. Twenty-six, 7-week-old male Wistar rats were randomly divided into the following 4 groups: (1) sedentary control (Con, n = 7), (2) exercise (Ex, n = 6), (3) caloric restriction (CR, n = 7), and (4) caloric restriction and exercise training (ExCR, n = 6). Although Con and Ex rats were fed ad libitum over time, CR and ExCR rats consumed 40% less food compared to Con rats. Ex and ExCR rats underwent low-intensity treadmill running (30 min/day, 5 days/week). Forty-eight hours after the termination of the 12-week intervention, rats were sacrificed and the hippocampus was quickly dissected for measuring BDNF expression and markers of oxidative stress, including 4-hydroxy-2-nonenal (4-HNE). Hippocampal BDNF expression was significantly increased in Ex compared to Con rats (p = 0.007), whereas the exercise-induced increase in BDNF was completely suppressed by a combination with caloric restriction. Furthermore, we observed a significant relationship between hippocampal BDNF and 4-HNE expression (r = 0.725, p < 0.001). Our findings indicate that exercise training combined with caloric restriction might not have a synergistic effect on hippocampal BDNF expression in young rats. Moreover, exercise-induced oxidative stress can trigger BDNF expression in the hippocampus.
Xanthophylls have been attracting attention as phytochemicals with antioxidant activity and various beneficial effects demonstrated by randomized clinical trials. Ripe red paprika has high xanthophyll content and is a valuable source of dietary xanthophylls. Our previous study revealed that paprika xanthophylls were detected in the plasma of healthy volunteers after oral administration and preferentially accumulated in erythrocytes, suggesting a potential beneficial effect on erythrocytes. The present study was performed to investigate the effect of paprika xanthophyll supplementation on respiratory parameters in athletes performing treadmill exercise. In a randomized, double-blind, placebo-controlled, parallel group study, 14 athletes were assigned to daily intake of a drink containing 9.0 mg of paprika xanthophylls or a placebo drink. Before and after the 4-week intervention period, blood samples were collected to measure plasma carotenoid levels. The athletes also performed treadmill exercise (12 km/hr for 20 min) before and after the 4-week intervention period, and respiratory parameters were analyzed. After 4 weeks, the paprika xanthophyll group had significantly higher levels of total plasma xanthophylls and total plasma carotenoids (p = 0.014 and 0.043, respectively) than the placebo group. VO2, VCO2, and VE were significantly lower in the paprika xanthophyll group than the placebo group. These results suggest that paprika xanthophyll supplementation allowed athletes to perform exercise at a set intensity with lower oxygen uptake. Subjective fatigue after exercise was also significantly less severe in the paprika xanthophyll group.