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Molecules (Basel, Switzerland) Feb 2021Duchenne muscular dystrophy (DMD) is a progressive fatal neuromuscular disorder with no cure. Therapies to restore dystrophin deficiency have been approved in some...
Duchenne muscular dystrophy (DMD) is a progressive fatal neuromuscular disorder with no cure. Therapies to restore dystrophin deficiency have been approved in some jurisdictions but long-term effectiveness is yet to be established. There is a need to develop alternative strategies to treat DMD. Resveratrol is a nutraceutical with anti-inflammatory properties. Previous studies have shown high doses (100-400 mg/kg bodyweight/day) benefit mice. We treated 4-week-old and wildtype mice with a lower dose of resveratrol (5 mg/kg bodyweight/day) for 15 weeks. Voluntary exercise was used to test if a lower dosage than previously tested could reduce exercise-induced damage where a greater inflammatory infiltrate is present. We found resveratrol promoted skeletal muscle hypertrophy in wildtype mice. In dystrophic muscle, resveratrol reduced exercise-induced muscle necrosis. Gene expression of immune cell markers, CD86 and CD163 were reduced; however, signalling targets associated with resveratrol's mechanism of action including Sirt1 and NF-κB were unchanged. In conclusion, a lower dose of resveratrol compared to the dosage used by other studies reduced necrosis and gene expression of inflammatory cell markers in dystrophic muscle suggesting it as a therapeutic candidate for treating DMD.
Topics: Animals; Biomarkers; Gene Expression Regulation; Hypertrophy; Inflammation; Mice; Muscle, Skeletal; Necrosis; Resveratrol
PubMed: 33561994
DOI: 10.3390/molecules26040853 -
Journal of Applied Physiology... Mar 2021In this study, we examined the effect of β-agonist salbutamol at oral doses during a period of resistance training on sprint performance, quadriceps contractile... (Randomized Controlled Trial)
Randomized Controlled Trial
β-Adrenergic agonist salbutamol augments hypertrophy in MHCIIa fibers and sprint mean power output but not muscle force during 11 weeks of resistance training in young men.
In this study, we examined the effect of β-agonist salbutamol at oral doses during a period of resistance training on sprint performance, quadriceps contractile function, skeletal muscle hypertrophy, fiber type composition, maximal activity of enzymes of importance for anaerobic energy turnover, and sarcoplasmic reticulum Ca handling in young men. Twenty-six men (23 ± 2 yr; means ± SD) were randomized to daily intake of oral salbutamol (16 mg/day; RES+SAL) or placebo (RES) during 11 wk of full-body resistance training 3 times/wk. Mean power output during 10-s maximal cycling increased more ( = 0.027) in RES+SAL (+12%) than in RES (+7%), whereas peak power output increased similarly (RES+SAL: +8%; RES: +7%; = 0.400). Quadriceps dynamic peak torque and maximal voluntary isometric torque increased by 13 and 14% ( ≤ 0.001) in RES+SAL and 13 and 13% ( ≤ 0.001) in RES, respectively. Myosin heavy-chain (MHC) isoform distribution transitioned from MHCI and MHCIIx toward MHCIIa in RES+SAL ( = 0.002), but not in RES ( = 0.323). MHCIIa cross-sectional-area increased more ( = 0.040) in RES+SAL (+35%) than RES (+21%). Sarcoplasmic reticulum Ca release rate increased in both groups (RES+SAL: +9%, = 0.048; RES: +13%, = 0.008), whereas Ca-uptake rate increased only in RES (+12%, = 0.022) but was not different from the nonsignificant change in RES+SAL (+2%, = 0.484). Maximal activity of lactate dehydrogenase increased only in RES+SAL (+13%, = 0.008). Muscle content of the dihydropyridine receptor, ryanodine receptor 1, and sarcoplasmic reticulum Ca-ATPase isoform 1 and 2 did not change with the intervention in either group ( ≥ 0.100). These observations indicate that the enhancement of sprint mean power output induced by salbutamol is at least partly attributed to greater hypertrophy of MHCIIa fibers and transition toward the MHCIIa isoform. Here, we show that daily oral treatment with selective β-agonist salbutamol induces muscle fiber isoform transition from myosin-heavy-chain (MHC)-I toward MHCIIa and augments hypertrophy of MHCIIa fibers during a period of resistance training. Compared with placebo, salbutamol enhanced sprint mean power output, whereas peak power output and measures of muscle strength increased similarly during the resistance training period despite augmented hypertrophy with salbutamol. Thus, salbutamol is a muscle anabolic drug that can enhance sprint ability adaptations to resistance training.
Topics: Adrenergic Agonists; Adult; Albuterol; Cross-Sectional Studies; Humans; Hypertrophy; Male; Muscle Fibers, Skeletal; Muscle, Skeletal; Resistance Training; Young Adult
PubMed: 33357007
DOI: 10.1152/japplphysiol.00553.2020 -
American Journal of Physiology. Cell... Nov 2020Human skeletal muscle is a heterogeneous tissue composed of multiple fiber types that express unique contractile and metabolic properties. While analysis of mixed fiber... (Review)
Review
Human skeletal muscle is a heterogeneous tissue composed of multiple fiber types that express unique contractile and metabolic properties. While analysis of mixed fiber samples predominates and holds value, increasing attention has been directed toward studying proteins segregated by fiber type, a methodological distinction termed "fiber type-specific." Fiber type-specific protein studies have the advantage of uncovering key molecular effects that are often missed in mixed fiber homogenate studies but also require greater time and resource-intensive methods, particularly when applied to human muscle. This review summarizes and compares current methods used for fiber type-specific protein analysis, highlighting their advantages and disadvantages for human muscle studies, in addition to recent advances in these techniques. These methods can be grouped into three categories based on the initial processing of the tissue: ) muscle-specific fiber homogenates, ) cross sections of fiber bundles, and ) isolated single fibers, with various subtechniques for performing fiber type identification and protein quantification. The relative implementation for each unique methodological approach is analyzed from 83 fiber type-specific studies of proteins in live human muscle found in the literature to date. These studies have investigated several proteins involved in a wide range of cellular functions that are important to muscle tissue. The second half of this review summarizes key findings from this ensemble of fiber type-specific human protein studies. We highlight examples of where this analytical approach has helped to improve understanding of important physiological topics such as insulin sensitivity, muscle hypertrophy, muscle fatigue, and adaptation to different exercise programs.
Topics: Complex Mixtures; Exercise; Gene Expression; Humans; Hypertrophy; Insulin Resistance; Microtomy; Muscle Fatigue; Muscle Fibers, Fast-Twitch; Muscle Fibers, Slow-Twitch; Muscle Proteins; Muscular Diseases; Organ Specificity; Physical Endurance
PubMed: 32783659
DOI: 10.1152/ajpcell.00107.2020 -
Journal of Applied Physiology... Apr 2023There is some evidence that the age-associated change in skeletal muscle mass is muscle specific, yet the number of specific muscles that have been studied to form our...
There is some evidence that the age-associated change in skeletal muscle mass is muscle specific, yet the number of specific muscles that have been studied to form our understanding in this area is limited. In addition, few aging investigations have examined multiple muscles in the same individuals. This longitudinal investigation compared changes in skeletal muscle size via computed tomography of the quadriceps (rectus femoris, vastus lateralis, vastus medialis, and vastus intermedius), hamstrings (biceps femoris short and long heads, semitendinosus, and semimembranosus), psoas, rectus abdominis, lateral abdominals (obliques and transversus abdominis), and paraspinal muscles (erector spinae and multifidi) of older individuals from the Health, Aging, and Body Composition (Health ABC) study at baseline and 5.0 ± 0.1 years later ( = 469, 73 ± 3 yr and 78 ± 3 yr, 49% women, 33% black). Skeletal muscle size decreased ( < 0.05) in quadriceps (-3.3%), hamstrings (-5.9%), psoas (-0.4%), and rectus abdominis (-7.0%). The hamstrings and rectus abdominis atrophied approximately twice as much as the quadriceps ( < 0.05), whereas the quadriceps atrophied substantially more than the psoas ( < 0.05). The lateral abdominals (+5.9%) and paraspinals (+4.3%) hypertrophied ( < 0.05) to a similar degree ( > 0.05) over the 5 years. These data suggest that older individuals experience skeletal muscle atrophy and hypertrophy in a muscle group-specific fashion in the eighth decade, a critical time period in the aging process. A broader understanding of muscle group-specific skeletal muscle aging is needed to better guide exercise programs and other interventions that mitigate decrements in physical function with aging. These longitudinal analyses of six muscle groups in septuagenarians provide novel information on the muscle group-specific aging process. Although the quadriceps, hamstrings, psoas, and rectus abdominis atrophied with different magnitudes, the lateral abdominals and paraspinals hypertrophied over the 5 years. These findings contribute to a better understanding of the skeletal muscle aging process and highlight the need to complete studies in this area with a muscle-specific focus.
Topics: Humans; Female; Male; Longitudinal Studies; Muscle, Skeletal; Quadriceps Muscle; Muscular Atrophy; Aging; Hypertrophy
PubMed: 36892888
DOI: 10.1152/japplphysiol.00769.2022 -
Journal of Applied Physiology... Jun 2019Previously trained mouse muscles acquire strength and volume faster than naïve muscles; it has been suggested that this is related to increased myonuclear density. The...
Previously trained mouse muscles acquire strength and volume faster than naïve muscles; it has been suggested that this is related to increased myonuclear density. The present study aimed to determine whether a previously strength-trained leg (mem-leg) would respond better to a period of strength training than a previously untrained leg (con-leg). Nine men and 10 women performed unilateral strength training (T1) for 10 wk, followed by 20 wk of detraining (DT) and a 5-wk bilateral retraining period (T2). Muscle biopsies were taken before and after each training period and analyzed for myonuclear number, fiber volume, and cross-sectional area (CSA). Ultrasound and one repetition of maximum leg extension were performed to determine muscle thickness (MT) and strength. CSA (~17%), MT (~10%), and strength (~20%) increased during T1 in the mem-leg. However, the myonuclear number and fiber volume did not change. MT and CSA returned to baseline values during DT, but strength remained elevated (~60%), supporting previous findings of a long-lasting motor learning effect. MT and strength increased similarly in the mem-leg and con-leg during T2, whereas CSA, fiber volume, and myonuclear number remained unaffected. In conclusion, training response during T2 did not differ between the mem-leg and con-leg. However, this does not discount the existence of human muscle memory, since no increase in the number of myonuclei was detected during T1 and no clear detraining effect was observed for cell size during DT; thus, the present data did not allow for a rigorous test of the muscle memory hypothesis. If a long-lasting intramuscular memory exists in humans, this will affect strength-training advice for both athletes and the public. Based on animal experiments, we hypothesized that such a memory exists and that it is related to the myonuclear number. However, a period of unilateral strength training, followed by detraining, did not increase the myonuclear number. The training response, during a subsequent bilateral retraining period, was not enhanced in the previously trained leg.
Topics: Adaptation, Physiological; Adult; Female; Humans; Hypertrophy; Male; Muscle Fibers, Skeletal; Muscle Strength; Resistance Training
PubMed: 30991013
DOI: 10.1152/japplphysiol.00917.2018 -
American Journal of Physiology. Cell... Sep 2022Multinuclear muscle fibers are the most voluminous cells in skeletal muscle and the primary drivers of growth in response to loading. Outside the muscle fiber, however,... (Review)
Review
Multinuclear muscle fibers are the most voluminous cells in skeletal muscle and the primary drivers of growth in response to loading. Outside the muscle fiber, however, is a diversity of mononuclear cell types that reside in the extracellular matrix (ECM). These muscle-resident cells are exercise-responsive and produce the scaffolding for successful myofibrillar growth. Without proper remodeling and maintenance of this ECM scaffolding, the ability to mount an appropriate response to resistance training in adult muscles is severely hindered. Complex cellular choreography takes place in muscles following a loading stimulus. These interactions have been recently revealed by single-cell explorations into muscle adaptation with loading. The intricate ballet of ECM remodeling involves collagen production from fibrogenic cells and ECM modifying signals initiated by satellite cells, immune cells, and the muscle fibers themselves. The acellular collagen-rich ECM is also a mechanical signal-transducer and rich repository of growth factors that may directly influence muscle fiber hypertrophy once liberated. Collectively, high levels of collagen expression, deposition, and turnover characterize a well-trained muscle phenotype. The purpose of this review is to highlight the most recent evidence for how the ECM and its cellular components affect loading-induced muscle hypertrophy. We also address how the muscle fiber may directly take part in ECM remodeling, and whether ECM dynamics are rate limiting for muscle fiber growth.
Topics: Collagen; Extracellular Matrix; Humans; Hypertrophy; Muscle Fibers, Skeletal; Muscle, Skeletal
PubMed: 35876284
DOI: 10.1152/ajpcell.00200.2022 -
International Journal of Molecular... Sep 2020Nearly 100 years ago, Otto Warburg investigated the metabolism of growing tissues and discovered that tumors reprogram their metabolism. It is poorly understood whether...
Nearly 100 years ago, Otto Warburg investigated the metabolism of growing tissues and discovered that tumors reprogram their metabolism. It is poorly understood whether and how hypertrophying muscle, another growing tissue, reprograms its metabolism too. Here, we studied pyruvate kinase muscle (PKM), which can be spliced into two isoforms (PKM1, PKM2). This is of interest, because PKM2 redirects glycolytic flux towards biosynthetic pathways, which might contribute to muscle hypertrophy too. We first investigated whether resistance exercise changes PKM isoform expression in growing human skeletal muscle and found that PKM2 abundance increases after six weeks of resistance training, whereas PKM1 decreases. Second, we determined that expression is higher in fast compared to slow fiber types in rat skeletal muscle. Third, by inducing hypertrophy in differentiated C2C12 cells and by selectively silencing and/or with siRNA, we found that PKM2 limits myotube growth. We conclude that PKM2 contributes to hypertrophy in C2C12 myotubes and indicates a changed metabolic environment within hypertrophying human skeletal muscle fibers. PKM2 is preferentially expressed in fast muscle fibers and may partly contribute to the increased potential for hypertrophy in fast fibers.
Topics: Adult; Carrier Proteins; Cell Line; Humans; Hypertrophy; Male; Membrane Proteins; Muscle Fibers, Fast-Twitch; Muscle Fibers, Slow-Twitch; Resistance Training; Thyroid Hormones; Thyroid Hormone-Binding Proteins
PubMed: 32992783
DOI: 10.3390/ijms21197062 -
Journal of Applied Physiology... Sep 2020The ability to genetically manipulate mice allows for gain- and loss-of-function in vivo, making them an ideal model for elucidating mechanisms of skeletal muscle mass... (Review)
Review
The ability to genetically manipulate mice allows for gain- and loss-of-function in vivo, making them an ideal model for elucidating mechanisms of skeletal muscle mass regulation. Combining genetic models with mechanical muscle loading enables identification of specific factors involved in the hypertrophic response as well as the ability to test the requirement of those factors for adaptation, thereby informing performance and therapeutic interventions. Until recently, approaches for inducing mechanically mediated muscle hypertrophy (i.e., resistance-training analogs) have been limited and considered "nontranslatable" to humans. This mini-review outlines recent translational advances in loading-mediated strategies for inducing muscle hypertrophy in mice, and highlights the advantages and disadvantages of each method. The skeletal muscle field is poised for new breakthroughs in understanding mechanisms regulating load-induced muscle growth given the numerous murine tools that have very recently been described.
Topics: Adaptation, Physiological; Animals; Hypertrophy; Mice; Muscle, Skeletal; Resistance Training
PubMed: 32673155
DOI: 10.1152/japplphysiol.00319.2020 -
American Journal of Physiology.... Dec 2015Skeletal muscle is a direct target for vitamin D. Observational studies suggest that low 25[OH]D correlates with functional recovery of skeletal muscle following... (Randomized Controlled Trial)
Randomized Controlled Trial
Skeletal muscle is a direct target for vitamin D. Observational studies suggest that low 25[OH]D correlates with functional recovery of skeletal muscle following eccentric contractions in humans and crush injury in rats. However, a definitive association is yet to be established. To address this gap in knowledge in relation to damage repair, a randomised, placebo-controlled trial was performed in 20 males with insufficient concentrations of serum 25(OH)D (45 ± 25 nmol/l). Prior to and following 6 wk of supplemental vitamin D3 (4,000 IU/day) or placebo (50 mg of cellulose), participants performed 20 × 10 damaging eccentric contractions of the knee extensors, with peak torque measured over the following 7 days of recovery. Parallel experimentation using isolated human skeletal muscle-derived myoblast cells from biopsies of 14 males with low serum 25(OH)D (37 ± 11 nmol/l) were subjected to mechanical wound injury, which enabled corresponding in vitro studies of muscle repair, regeneration, and hypertrophy in the presence and absence of 10 or 100 nmol 1α,25(OH)2D3. Supplemental vitamin D3 increased serum 25(OH)D and improved recovery of peak torque at 48 h and 7 days postexercise. In vitro, 10 nmol 1α,25(OH)2D3 improved muscle cell migration dynamics and resulted in improved myotube fusion/differentiation at the biochemical, morphological, and molecular level together with increased myotube hypertrophy at 7 and 10 days postdamage. Together, these preliminary data are the first to characterize a role for vitamin D in human skeletal muscle regeneration and suggest that maintaining serum 25(OH)D may be beneficial for enhancing reparative processes and potentially for facilitating subsequent hypertrophy.
Topics: Administration, Oral; Adolescent; Adult; Dietary Supplements; Humans; Hypertrophy; Muscle, Skeletal; Physical Exertion; Placebo Effect; Regeneration; Systems Biology; Vitamin D; Young Adult
PubMed: 26506852
DOI: 10.1152/ajpendo.00375.2015 -
The Biochemical Journal Aug 1986The patterns of myosin isoenzymes in fast- and slow-twitch muscles of the rat hindlimb were studied, by pyrophosphate/polyacrylamide-gel electrophoresis, with...
The patterns of myosin isoenzymes in fast- and slow-twitch muscles of the rat hindlimb were studied, by pyrophosphate/polyacrylamide-gel electrophoresis, with hypertrophy (induced by synergist removal) and with spontaneous running exercise of 4 and 11 weeks duration. At 11 weeks, changes with hypertrophy in the slow-twitch soleus, composed of greater than 95% SM2 (slow myosin 2) in normal muscles, were minor, and consisted of an increase in the SM1 and SM1', and a loss of intermediate myosin (IM), an isoenzyme characteristic of Type IIa fibres [Fitzsimons & Hoh (1983) J. Physiol. (London) 343, 539-550]. The changes were dramatic, however, in the fast-twitch plantaris muscle. There was a 3-fold increase in the proportion of SM. In addition, IM became the predominant isoenzyme in the profile of hypertrophied plantaris by 4 weeks. These increases were balanced by decreases in the proportion of FM2 (fast myosin 2), with FM1 completely absent from the profile at 11 weeks. The changes in the plantaris with exercise were similar in direction but not as extensive as those with hypertrophy, and FM1 remained present at control levels throughout the study. When hypertrophy and exercise were combined, the increase in slow myosin was equal to the sum of the increases with each treatment alone. Changes at 4 weeks were intermediate between those of control and 11-week muscles. Peptide mapping of individual myosin isoenzymes showed that the heavy chains of IM were different from either fast or slow heavy chains. Furthermore, IM was found to be composed of a mixture of fast and slow light chains. These changes suggest that a transformation of myosin from fast to slow isoforms was in progress in the plantaris in response to hypertrophy, via a Type-IIa-myosin (IM) intermediate stage, a phenomenon similar to that occurring in chronically stimulated fast muscles during fast-to-slow transformation [Brown, Salmons & Whalen (1983) J. Biol. Chem. 258, 14686-14692].
Topics: Adenosine Triphosphatases; Animals; Electrophoresis, Polyacrylamide Gel; Female; Hypertrophy; Isoenzymes; Muscles; Myosins; Organ Size; Peptide Mapping; Physical Exertion; Rats; Rats, Inbred Strains
PubMed: 2948496
DOI: 10.1042/bj2380055