Peroxisome proliferator-activated receptor ␥ co-activator 1␣ (PGC-1␣) promotes mitochondrial biogenesis and slow fiber formation in skeletal muscle. We hypothesized that activation of the p38 mitogen-activated protein kinase (MAPK) pathway in response to increased muscle activity stimulated Pgc-1␣ gene transcription as part of the mechanisms for skeletal muscle adaptation. Here we report that a single bout of voluntary running induced a transient increase of Pgc-1␣ mRNA expression in mouse plantaris muscle, concurrent with an activation of the p38 MAPK pathway. Activation of the p38 MAPK pathway in cultured C2C12 myocytes stimulated Pgc-1␣ promoter activity, which could be blocked by the specific inhibitors of p38, SB203580 and SB202190, or a dominant negative p38. Furthermore, the p38-mediated increase in Pgc-1␣ promoter activity was enhanced by increased expression of the downstream transcription factor ATF2 and completely blocked by ATF2⌬N, a dominant negative ATF2. Skeletal muscle-specific expression of a constitutively active activator of p38, MKK6E, in transgenic mice resulted in enhanced Pgc-1␣ and cytochrome oxidase IV protein expression in fast-twitch skeletal muscles. These findings suggest that contractile activity-induced activation of the p38 MAPK pathway promotes Pgc-1␣ gene expression and skeletal muscle adaptation.

Peroxisome proliferator-activated receptor-␥ co-activator 1␣ (PGC1␣) is a promiscuous co-activator that plays a key role in regulating mitochondrial biogenesis and fuel homeostasis. Emergent evidence links decreased skeletal muscle PGC1␣ activity and coincident impairments in mitochondrial performance to the development of insulin resistance in humans. Here we used rodent models to demonstrate that muscle mitochondrial efficiency is compromised by diet-induced obesity and is subsequently rescued by exercise training. Chronic high fat feeding caused accelerated rates of incomplete fatty acid oxidation and accumulation of ␤-oxidative intermediates. The capacity of muscle mitochondria to fully oxidize a heavy influx of fatty acid depended on factors such as fiber type and exercise training and was positively correlated with expression levels of PGC1␣. Likewise, an efficient lipid-induced substrate switch in cultured myocytes depended on adenovirus-mediated increases in PGC1␣ expression. Our results supported a novel paradigm in which a high lipid supply, occurring under conditions of low PGC1␣, provokes a disconnect between mitochondrial ␤-oxidation and tricarboxylic acid cycle activity. Conversely, the metabolic remodeling that occurred in response to PGC1␣ overexpression favored a shift from incomplete to complete ␤-oxidation. We proposed that PGC1␣ enables muscle mitochondria to better cope with a high lipid load, possibly reflecting a fundamental metabolic benefit of exercise training.Obesity and type 2 diabetes are two closely associated diseases that continue to affect Westernized societies at epidemic rates (1). Results from both epidemiological and animal studies suggest that the risk of developing these diseases is increased by consumption of a high fat diet (2), which has been attributed in part to increased intramuscular triacylglycerol storage and adverse changes in skeletal muscle energy metabolism (3). Moreover, mounting evidence from animal and cellbased models indicates that lipid oversupply to skeletal muscle results in functional perturbations that eventually manifest as impaired insulin action (2, 4, 5). Together, these and other reports have established a compelling connection between muscle lipid dysregulation and impaired metabolic control at both the cellular and systemic levels. Despite intense investigation, a clear understanding of the biochemical and molecular mechanisms that mediate lipid-induced muscle dysfunction has remained elusive.Similar to high fat feeding, exercise training increases skeletal muscle supply and storage of lipid substrates (6). However, in contrast to the adverse events provoked by a high fat diet, exercise is known to promote muscle as well as whole body metabolic fitness (7). These observations suggest that physical activity somehow enhances the capacity of the muscle to tolerate and/or adapt to a high lipid load. Indeed, contractile activity leads to dramatic adjustments in oxidative fuel metabolism that are largely mediated by an increase in muscle mitochondria...

a b s t r a c tMesenchymal stem cell (MSC) transplantation is used for treatment of many diseases. The paracrine role of MSCs in tissue regeneration is attracting particular attention. We investigate the role of MSC exosomes in skeletal muscle regeneration. MSC exosomes promote myogenesis and angiogenesis in vitro, and muscle regeneration in an in vivo model of muscle injury. Although MSC exosomes had low concentrations of muscle-repair-related cytokines, a number of repair-related miRNAs were identified. This study suggests that the MSC-derived exosomes promote muscle regeneration by enhancing myogenesis and angiogenesis, which is at least in part mediated by miRNAs such as miR-494.

Mohawk (Mkx) is a member of the Three Amino acid Loop Extension superclass of atypical homeobox genes that is expressed in developing tendons. To investigate the in vivo functions of Mkx, we generated Mkx −/− mice. These mice had hypoplastic tendons throughout the body. Despite the reduction in tendon mass, the cell number in tail tendon fiber bundles was similar between wild-type and Mkx −/− mice. We also observed small collagen fibril diameters and a down-regulation of type I collagen in Mkx −/− tendons. These data indicate that Mkx plays a critical role in tendon differentiation by regulating type I collagen production in tendon cells.T endons are dense, fibrous connective tissues that connect muscle to bone, transmitting the forces that allow for body movement (1). Tendon damage from overuse or degeneration due to aging is a common clinical problem because damaged tendon tissue heals very slowly and rarely recovers completely (2). The establishment of new therapies, such as regenerative medicine, for injured tendons has been delayed by a limited understanding of tendon biology (1, 3).Tendons are composed primarily of collagen fibrils that cross-link to each other to form fibers (4). A small number of tendon cells reside between parallel chains of these fibrils and synthesize the specific ECM that contains collagens and proteoglycans (4, 5). The elasticity of tendons is provided by the large amount of collagen, predominantly type I collagen and small amounts of other collagens, including types III, IV, V, and VI (4, 6-9). The proteoglycans found in tendons, including decorin, fibromodulin, biglycan, and lumican, act to lubricate and organize collagen fiber bundles (4, 5). Targeted disruption of these proteoglycans in mice leads to abnormal collagen fibrils in tendons (3, 10-13). Tendon disruptions have also been described in patients with defects in collagen production, such as Ehlers-Danlos Syndrome, in which the type I collagen gene is mutated (14). These studies indicate that the ability of tendon cells to produce ECM is important for tendon formation.Recently, it was reported that Scleraxis (Scx), a basic helix-loophelix (bHLH) transcription factor expressed in the tendon progenitors and cells of all tendon tissues (15, 16), is essential for tendon differentiation. Scx knockout mice show severe disruption of force-transmitting tendons, although ligaments, which are tissues connecting bone to bone that closely resemble tendons in their components, and short-range anchoring tendons are not affected (17). It was also reported that Scx positively regulates the expression of type I collagen, a main ECM component of tendons (18). However, the type I collagen does not completely disappear from the tendons of Scx knockout mice (17), suggesting the presence of other regulatory factors for type I collagen. The tendon differentiation mechanisms remain largely unknown, with Scx being the only known transcription factor regulating tendon differentiation.Mohawk (Mkx; also known as Irxl1) is the sole member of a newly c...

Key points• The discovery of microRNAs (miRNAs) has established new mechanisms that control health, but little is known about the regulation of skeletal muscle miRNAs in response to exercise.• This study investigated components of the miRNA biogenesis pathway (Drosha, Dicer and Exportin-5), muscle enriched miRNAs, (miR-1, -133a, -133b and 206), and several miRNAs dysregulated in muscle myopathies, and showed that 3 h following an acute exercise bout, Drosha, Dicer and Exportin-5, as well as miR-1, -133a, -133-b and miR-181a were all increased, while miR-9, -23a, -23b and -31 were decreased.• Short-term training increased miR-1 and miR-29b, while miR-31 remained decreased.• Negative correlations were observed between miR-9 and HDAC4 protein, miR-31 and HDAC4protein and between miR-31 and NRF1 protein, 3 h after exercise.• miR-31 binding to the HDAC4 and NRF1 3 untranslated region (UTR) reduced luciferase reporter activity.• Exercise rapidly and transiently regulates several miRNA species potentially involved in the regulation of skeletal muscle regeneration, gene transcription and mitochondrial biogenesis.Abstract The identification of microRNAs (miRNAs) has established new mechanisms that control skeletal muscle adaptation to exercise. The present study investigated the mRNA regulation of components of the miRNA biogenesis pathway (Drosha, Dicer and Exportin-5), muscle enriched miRNAs, (miR-1, -133a, -133b and -206), and several miRNAs dysregulated in muscle myopathies (miR-9, -23, -29, -31 and -181). Measurements were made in muscle biopsies from nine healthy untrained males at rest, 3 h following an acute bout of moderate-intensity endurance cycling and following 10 days of endurance training. Bioinformatics analysis was used to predict potential miRNA targets. In the 3 h period following the acute exercise bout, Drosha, Dicer and Exportin-5, as well as miR-1, -133a, -133-b and -181a were all increased. In contrast miR-9, -23a, -23b and -31 were decreased. Short-term training increased miR-1 and -29b, while miR-31 remained decreased. Negative correlations were observed between miR-9 and HDAC4 protein (r = −0.71; P = 0.04), miR-31 and HDAC4 protein (r = −0.87; P = 0.026) and miR-31 and NRF1 protein (r = −0.77; P = 0.01) 3 h following exercise. miR-31 binding to the HDAC4 and NRF1 3 untranslated region (UTR) reduced luciferase reporter activity. Exercise rapidly and transiently regulates several miRNA species in muscle. Several of these miRNAs may be involved in the regulation of skeletal muscle regeneration, gene transcription and mitochondrial biogenesis. Identifying endurance exercise-mediated stress signals regulating skeletal muscle miRNAs, as well as validating their targets and regulatory pathways post exercise, will advance our understanding of their potential role/s in human health.

Muscle atrophy is caused by accelerated protein degradation and occurs in many pathological states. Two muscle-specific ubiquitin ligases, MAFbx/atrogin-1 and muscle RING-finger 1 (MuRF1), are prominently induced during muscle atrophy and mediate atrophy-associated protein degradation. Blocking the expression of these two ubiquitin ligases provides protection against muscle atrophy. Here we report that miR-23a suppresses the translation of both MAFbx/atrogin-1 and MuRF1 in a 3-UTR-dependent manner. Ectopic expression of miR-23a is sufficient to protect muscles from atrophy in vitro and in vivo. Furthermore, miR-23a transgenic mice showed resistance against glucocorticoid-induced skeletal muscle atrophy. These data suggest that suppression of multiple regulators by a single miRNA can have significant consequences in adult tissues.

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Background: The immune system declines in efficiency with advancing age, making the elderly less resistant to pathogenic microorganisms. Upper respiratory tract infection (URTI) is a common illness. Recent studies have shown that suppression of secretory immunoglobulin A (SIgA) is associated with increased incidence of URTI. Objective: To assess the effect of exercise on salivary SIgA in elderly subjects. Methods: Forty five elderly subjects (18 men, 27 women; mean (SD) age 64.9 (8.4) years) performed both 60 minute resistance and 60 minute moderate endurance training a week for 12 months. Saliva samples were obtained before training, and at four and 12 months during the training period. Salivary SIgA concentrations were measured by enzyme linked immunosorbent assay, and the SIgA secretion rate was calculated. Results: SIgA concentrations before training, and at four and 12 months during training were 24.7 (14.4), 27.2 (14.2), and 33.8 (18.5) µg/ml respectively. SIgA secretion rates were 29.5 (26.0), 33.8 (27.2) and 46.5 (35.1) µg/min respectively. The results indicate that both the concentration and secretion rate of SIgA significantly (p<0.01) increased during 12 months of exercise in these elderly subjects. Conclusion: Regular moderate exercise seems to enhance mucosal immune function in elderly subjects.