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Abstract All-trans retinoic acid (ATRA) has been associated with various physiological phenomenon in mammalian adipose tissue and skeletal muscle. We hypothesized that ATRA may affect skeletal muscle fiber type in bovine satellite cell culture through various transcriptional processes. Bovine primary satellite cell (BSC) culture experiments were conducted to determine dose effects of ATRA on expression of genes and protein levels related to skeletal muscle fiber type and metabolism. The semimembranosus from crossbred steers (n = 2 steers), aged approximately 24 mo, were used to isolate BSC for 3 separate assays. Myogenic differentiation was induced using 3% horse serum upon cultured BSC with increasing doses (0, 1, 10, 100, and 1,000 nM) of ATRA. After 96 h of incubation, cells were harvested and used to measure the gene expression of protein kinase B (Akt), AMP-activated protein kinase alpha (AMPK), glucose transporter 4 (GLUT4), myogenin, lipoprotein lipase (LPL), myosin heavy chain (MHC) I, MHC IIA, MHC IIX, insulin like growth factor-1 (IGF-1), Peroxisome proliferator activated receptor gamma (PPARγ), PPARδ, and Smad transcription factor 3 (SMAD3) mRNA relative to ribosomal protein subunit 9 (RPS9). The mRNA expression of LPL was increased (P < 0.05) with 100 and 1,000 nM of ATRA. Expression of GLUT4 was altered (P < 0.05) by ATRA. The treatment of ATRA (1,000 nM) also increased (P < 0.05) mRNA gene expression of SMAD3. The gene expression of both PPARδ and PPARγ were increased (P < 0.05) with 1,000 nM of ATRA. Protein level of PPARδ was also affected (P < 0.05) by 1,000 nM of ATRA and resulted in a greater (P < 0.05) protein level of PPARδ compared to CON. All-trans retinoic acid (10 nM) increased gene expression of MHC I (P < 0.05) compared to CON. Expression of MHC IIA was also influenced (P < 0.05) by ATRA. The mRNA expression of MHC IIX was decreased (P < 0.05) with 100 and 1,000 nM of ATRA. In muscle cells, ATRA may cause muscle fibers to transition towards the MHC isoform that prefers oxidative metabolism, as evidenced by increased expression of genes associated with the MHC I isoform. These changes in MHC isoforms appeared to be brought about by changing PPARδ gene expression and protein levels.

Excessive training may limit physiological muscle adaptation through chronic oxidative stress and inflammation. Improper diet and overtraining may also disrupt intestinal homeostasis and in consequence enhance inflammation. Altogether, these factors may lead to an imbalance in the gut ecosystem, causing dysregulation of the immune system. Therefore, it seems to be important to optimize the intestinal microbiota composition, which is able to modulate the immune system and reduce oxidative stress. Moreover, the optimal intestinal microbiota composition may have an impact on muscle protein synthesis and mitochondrial biogenesis and function, as well as muscle glycogen storage. Aproperly balanced microbiome may also reduce inflammatory markers and reactive oxygen species production, which may further attenuate macromolecules damage. Consequently, supplementation with probiotics may have some beneficial effect on aerobic and anaerobic performance. The phenomenon of gut-muscle axis should be continuously explored to function maintenance, not only in athletes.

Skeletal muscle is a major metabolic organ that uses mostly glucose and lipids for energy production and has the capacity to remodel itself in response to exercise and fasting. Skeletal muscle wasting occurs in many diseases and during aging. Muscle wasting is often accompanied by chronic low-grade inflammation associated to inter- and intra-muscular fat deposition. During aging, muscle wasting is advanced due to increased movement disorders, as a result of restricted physical exercise, frailty, and the pain associated with arthritis. Muscle atrophy is characterized by increased protein degradation, where the ubiquitin-proteasomal and autophagy-lysosomal pathways, atrogenes, and growth factor signaling all play an important role. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family of transcription factors, which are activated by fatty acids and their derivatives. PPARs regulate genes that are involved in development, metabolism, inflammation, and many cellular processes in different organs. PPARs are also expressed in muscle and exert pleiotropic specialized responses upon activation by their ligands. There are three PPAR isotypes, viz., PPARα, -β/δ, and -γ. The expression of PPARα is high in tissues with effective fatty acid catabolism, including skeletal muscle. PPARβ/δ is expressed more ubiquitously and is the predominant isotype in skeletal muscle. It is involved in energy metabolism, mitochondrial biogenesis, and fiber-type switching. The expression of PPARγ is high in adipocytes, but it is also implicated in lipid deposition in muscle and other organs. Collectively, all three PPAR isotypes have a major impact on muscle homeostasis either directly or indirectly. Furthermore, reciprocal interactions have been found between PPARs and the gut microbiota along the gut-muscle axis in both health and disease. Herein, we review functions of PPARs in skeletal muscle and their interaction with the gut microbiota in the context of muscle wasting

The objective of this study was to examine the effect of nicotinamide riboside (NR) on pectoralis major muscle (PM) development and growth. Fertilized Cobb 500 broiler eggs (N = 156; average weight of 70.3 g) were ordered by weight, and within each four egg strata, eggs were randomly assigned to treatments within a 2 × 2 factorial arrangement. Factor 1 consisted of NR treatment with eggs receiving 0 or 250 mM NR. Factor 2 consisted of injection location, with treatments injected into either the yolk sac or albumen. Eggs were incubated at a temperature of 37 °C and a relative humidity of 40 ± 2% for the first 18 d of incubation and humidity was increased to 60 ± 2 °C for the final 3 d. On day 10 of incubation, eggs were injected in their designated location with 100 µL of 0.9% sterile saline containing the assigned NR dose. Chicks were hatched, euthanized, and morphometric measurements of the body and left PM were collected. The left PM was also analyzed for muscle fiber cross-sectional area (CSA) and density. There were no treatment × location or main effects for all body morphometric measurements (P > 0.07), except chest width of chicks from eggs injected in the yolk were wider (P = 0.01) than chicks from eggs injected in the albumen. There were only treatment × location interactions for PM weight and length (P < 0.01). When NR was injected into the albumen, PM weight did not differ (P = 0.09); however, when NR was injected into the yolk sac, PM weight increased (P < 0.01). When NR was injected into both locations, PM length increased (P < 0.01), but increased to a greater extent when NR was injected into the yolk sac. There were treatment main effects for PM width and depth (P < 0.01), with NR injected chicks having PM with greater width and depth. There were no treatment × location or main effects for PM fiber CSA (P > 0.06). There was a treatment × location interaction (P < 0.01) for fiber density. When NR was injected into the albumen, fiber density did not differ (P = 0.09); however, when NR was injected into the yolk sac, fiber density increased (P < 0.01). Injecting NR into the yolk sac of the developing embryo at day 10 of incubation increased PM development which was due to an increase in muscle density.

Skeletal muscle relies on resident muscle stem cells (MuSCs) for growth and repair. Aging and muscle diseases impair MuSC function, leading to stem cell exhaustion and regenerative decline that contribute to the progressive loss of skeletal muscle mass and strength. In the absence of clinically available nutritional solutions specifically targeting MuSCs, we used a human myogenic progenitor high-content imaging screen of natural molecules from food to identify nicotinamide (NAM) and pyridoxine (PN) as bioactive nutrients that stimulate MuSCs and have a history of safe human use. NAM and PN synergize via CK1-mediated cytoplasmic β-catenin activation and AKT signaling to promote amplification and differentiation of MuSCs. Oral treatment with a combination of NAM and PN accelerated muscle regeneration in vivo by stimulating MuSCs, increased muscle strength during recovery, and overcame MuSC dysfunction and regenerative failure during aging. Levels of NAM and bioactive PN spontaneously declined during aging in model organisms and interindependently associated with muscle mass and walking speed in a cohort of 186 aged people. Collectively, our results establish the NAM/PN combination as a nutritional intervention that stimulates MuSCs, enhances muscle regeneration, and alleviates age-related muscle decline with a direct opportunity for clinical translation.

Our study was to characterize sarcopenia in C57BL/6J mice using a clinically relevant definition to investigate the underlying molecular mechanisms. Aged male (23-32 months old) and female (27-28 months old) C57BL/6J mice were classified as non-, probable-, or sarcopenic based on assessments of grip strength, muscle mass, and treadmill running time, using 2 SDs below the mean of their young counterparts as cutoff points. A 9%-22% prevalence of sarcopenia was identified in 23-26 month-old male mice, with more severe age-related declines in muscle function than mass. Females aged 27-28 months showed fewer sarcopenic but more probable cases compared with the males. As sarcopenia progressed, a decrease in muscle contractility and a trend toward lower type IIB fiber size were observed in males. Mitochondrial biogenesis, oxidative capacity, and AMPK-autophagy signaling decreased as sarcopenia progressed in males, with pathways linked to mitochondrial metabolism positively correlated with muscle mass. No age- or sarcopenia-related changes were observed in mitochondrial biogenesis, OXPHOS complexes, AMPK signaling, mitophagy, or atrogenes in females. Our results highlight the different trajectories of age-related declines in muscle mass and function, providing insights into sex-dependent molecular changes associated with sarcopenia progression, which may inform the future development of novel therapeutic interventions.

Piezo1 forms mechanically activated nonselective cation channels that contribute to endothelial response to fluid flow. Here we reveal an important role in the control of capillary density. Conditional endothelial cell-specific deletion of Piezo1 in adult mice depressed physical performance. Muscle microvascular endothelial cell apoptosis and capillary rarefaction were evident and sufficient to account for the effect on performance. There was selective upregulation of thrombospondin-2 (TSP2), an inducer of endothelial cell apoptosis, with no effect on TSP1, a related important player in muscle physiology. TSP2 was poorly expressed in muscle endothelial cells but robustly expressed in muscle pericytes, in which nitric oxide (NO) repressed the Tsp2 gene without an effect on Tsp1. In endothelial cells, Piezo1 was required for normal expression of endothelial NO synthase. The data suggest an endothelial cell-pericyte partnership of muscle in which endothelial Piezo1 senses blood flow to sustain capillary density and thereby maintain physical capability.

Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by absence of the protein dystrophin, which acts as a structural link between the basal lamina and contractile machinery to stabilize muscle membranes in response to mechanical stress. In DMD, mechanical stress leads to exaggerated membrane injury and fiber breakdown, with fast fibers being the most susceptible to damage. A major contributor to this injury is muscle contraction, controlled by the motor protein myosin. However, how muscle contraction and fast muscle fiber damage contribute to the pathophysiology of DMD has not been well characterized. We explored the role of fast skeletal muscle contraction in DMD with a potentially novel, selective, orally active inhibitor of fast skeletal muscle myosin, EDG-5506. Surprisingly, even modest decreases of contraction (<15%) were sufficient to protect skeletal muscles in dystrophic mdx mice from stress injury. Longer-term treatment also decreased muscle fibrosis in key disease-implicated tissues. Importantly, therapeutic levels of myosin inhibition with EDG-5506 did not detrimentally affect strength or coordination. Finally, in dystrophic dogs, EDG-5506 reversibly reduced circulating muscle injury biomarkers and increased habitual activity. This unexpected biology may represent an important alternative treatment strategy for Duchenne and related myopathies.

BACKGROUNDMyotonic dystrophy type 1 (DM1) is a multisystemic, CTG repeat expansion disorder characterized by a slow, progressive decline in skeletal muscle function. A biomarker correlating RNA mis-splicing, the core pathogenic disease mechanism, and muscle performance is crucial for assessing response to disease-modifying interventions. We evaluated the Myotonic Dystrophy Splice Index (SI), a composite RNA splicing biomarker incorporating 22 disease-specific events, as a potential biomarker of DM1 muscle weakness.METHODSTotal RNA sequencing of tibialis anterior biopsies from 58 DM1 participants and 33 unaffected/disease controls was used to evaluate RNA splicing events across the disease spectrum. Targeted RNA sequencing was used to derive the SI from biopsies collected at baseline (n = 52) or a 3-month (n = 37) follow-up visit along with clinical measures of muscle performance.RESULTSThe SI demonstrated significant associations with measures of muscle strength and ambulation, including ankle dorsiflexion (ADF) strength and 10-meter run/fast walk (Pearson's r = -0.719 and -0.680, respectively). The SI was relatively stable over 3 months (intraclass correlation coefficient [ICC] = 0.863). Latent-class analysis identified 3 DM1 subgroups stratified by baseline SI (SIMild, SIModerate, and SISevere); SIModerate individuals had a significant increase in the SI over 3 months. Multiple linear regression modeling revealed that baseline ADF and SI were predictive of strength at 3 months (adjusted R² = 0.830).CONCLUSIONThe SI is a reliable biomarker that captures associations of RNA mis-splicing with physical strength and mobility and has prognostic utility to predict future function, establishing it as a potential biomarker for assessment of therapeutic target engagement.TRIAL REGISTRATIONClinicalTrials.gov NCT03981575.FUNDINGFDA (7R01FD006071), Myotonic Dystrophy Foundation, Wyck Foundation, Muscular Dystrophy Association, Novartis, Dyne, Avidity, PepGen, Takeda, Sanofi Genzyme, Pfizer, Arthex, and Vertex Pharmaceuticals.

Statins lower cholesterol, reducing the risk of heart disease, and are among the most frequently prescribed drugs. Approximately 10% of individuals develop statin-associated muscle symptoms (SAMS; myalgias, rhabdomyolysis, and muscle weakness), often rendering them statin intolerant. The mechanism underlying SAMS remains poorly understood. Patients with mutations in the skeletal muscle ryanodine receptor 1 (RyR1)/calcium release channel can be particularly intolerant of statins. High-resolution structures revealed simvastatin binding sites in the pore region of RyR1. Simvastatin stabilized the open conformation of the pore and activated the RyR1 channel. In a mouse expressing a mutant RyR1-T4709M found in a patient with profound statin intolerance, simvastatin caused muscle weakness associated with leaky RyR1 channels. Cotreatment with a Rycal drug that stabilizes the channel closed state prevented simvastatin-induced muscle weakness. Thus, statin binding to RyR1 can cause SAMS, and patients with RyR1 mutations may represent a high-risk group for statin intolerance.