The Snell dwarf mouse (Pit1(dw/dw)), an animal model of congenital combined pituitary hormone deficiency, displays skeletal muscle weakness. While enhanced responsivity to repeated exposures of muscle contractions have been documented for Snell dwarf mice, the response following single exposure to distinct contraction protocols remained uncharacterized. The purpose of this study was to investigate the muscle recovery of Snell dwarf and control littermate mice following a single exposure to two separate protocols-an intermittent slow velocity (30°/s) contraction protocol or a continuous rapid velocity (500°/s) contraction protocol. Following both protocols for control mice, torque values were 30% and 80% of pre-protocol values at 5 min and 3 days, respectively. At 10 days, performance returned to baseline for the 30°/s protocol and were depressed for the 500°/s protocol. For Snell dwarf mice following both protocols, torques were depressed to 5% of pre-protocol values at 5 min and returned to baseline by 3 days. Recovery following the 30°/s protocol for control mice and both protocols for Snell dwarf mice coincided with increased transcriptional output, upregulation of cytokine-mediated signaling genes, and a distribution shift to smaller muscle fibers with reduced area per nucleus. These features represent efficacious remodeling ubiquitous across distinct contraction paradigms in the context of the Pit1 mutation.

Rodent studies investigating long-term effects following termination of hypertrophy-inducing loading have predominantly involved exposures such as synergist ablation and weighted wheel running or ladder climbing. This research yielded a spectrum of results regarding the extent of detraining in terms of muscle mass and myonuclei number. The studies were also limited in their lack of sensitive performance measures and indirect relatedness to resistance training. Our research group developed and validated a relevant rat model of resistance-type training that induces increased muscle mass and performance. The aim of the present study was to determine to what extent these features persist 3 months following the termination of this training. While performance returned to baseline, muscle mass remained elevated by 17% and a shift in distribution to larger muscle fibers persisted. A 16% greater total RNA and heightened mRNA levels of ribosomal protein S6 kinases implicated preserved transcriptional output and ribosomal content. Remodeling of muscle fiber nuclei was consistent with these findings - increased nuclear number and a distribution shift to a more circular nuclear shape. These findings indicate that muscle mass detrains at a slower rate than performance and implicates multiple forms of myonuclear remodeling in muscle memory.

Snell dwarf mice with the Pit1(dw/dw) mutation are deficient in growth hormone, prolactin, and thyroid stimulating hormone and exhibit >40% lifespan extension. This longevity is accompanied by compromised muscular performance. However, research regarding young (3-month-old) Snell dwarf mice demonstrate exceptional responsivity to resistance-type training especially in terms of a shifted fiber type distribution and increased protein levels of vascular cell adhesion molecule-1 (VCAM-1), a possible mediator of such remodeling. In the present study, we investigated whether this responsiveness persists at 12 months of age. Unlike 12-month-old control mice, age-matched Snell dwarf mice remained resistant to training-induced maladaptive decreases in performance and muscle mass. This was accompanied by retainment of the remodeling capacity in muscles of Snell dwarf mice to increase VCAM-1 protein levels and a shift in myosin heavy chain (MHC) isoform distribution with training. Even decreasing training frequency for control mice, an alteration which protected muscles from maladaptation at 12 months of age, did not result in the overt remodeling observed for Snell dwarf mice. The results demonstrate a distinct remodeling response to resistance-type exercise operative in the context of the Pit1(dw/dw) mutation of long-lived Snell dwarf mice.

Efficacy of high-intensity resistance exercise becomes progressively compromised with aging. Previously, to investigate this, we developed a rodent model of high-intensity training consisting of stretch-shortening contractions (SSCs) and determined that following one month of training, young rats exhibit a robust stress response and 20% performance increase, whereas old rats display a muted stress response and 30% performance decrease. Whether these age-specific responses occur early in training and constitute primary factors in adaptation/maladaptation was not addressed. The aim of the present study was to characterize performance, remodeling, and stress response transcriptional profile 6-120 h following acute SSC exposure. For young rats, the stress response pathway was highly regulated (≥20 differentially expressed genes at each time point) and was accompanied by robust DNA demethylation, tissue remodeling, and isometric torque recovery. For old rats, a muted transcriptional profile (13 and 2 differentially expressed genes at 6 and 120 h, respectively) coincided with deficiencies in demethylation, muscle remodeling, and torque recovery. These findings occurred in the context of heightened chronic levels of stress response gene expression with aging. This demonstrates that age-related constitutive elevations in stress response gene expression was accompanied by diminished SSC-induced responsiveness in epigenomic regulation and tissue remodeling.

The purpose of this study was to characterize the growth and remodeling molecular signaling response in aged skeletal muscle following one month of "resistance-type exercise" training. Male Fisher344x Brown Norway hybrid rats aged 3 (young) and 30 months (old) underwent stretch-shortening contraction (SSC) loading two or three days per week; muscles were removed 72 hours post-training. Young rats SSC-loaded three (Y3x) or two days per week (Y2x) adapted via increased work performance. Old rats SSC-loaded three days per week (O3x) maladapted via decreased negative work; however, old rats SSC-loaded two days per week (O2x) adapted through improved negative and positive work. Y3x, Y2x, and O2x, but not O3x, displayed hypertrophy via larger fiber area and myonuclear domains. Y3x, Y2x, and O2x differentially expressed 19, 30, and 8 PI3K-AKT genes, respectively, whereas O3x only expressed two. Bioinformatics analysis revealed that rats in the adapting groups presented growth and remodeling processes (i.e. increased protein synthesis), whereas O3x demonstrated inflammatory signaling. In conclusion, reducing SSC-loading frequency in aged rodents positively influences the molecular signaling microenvironment, promoting muscle adaptation.

Snell dwarf mice (Pit1(dw/dw) ) exhibit deficiencies in growth hormone, prolactin, and thyroid stimulating hormone. Besides being an experimental model of hypopituitarism, these mice are long-lived (>40% lifespan extension) and utilized as a model of slowed/delayed aging. Whether this longevity is accompanied by a compromised quality of life in terms of muscular performance has not yet been characterized. In this study, we investigated nontrained and trained muscles 1 month following a general validated resistance-type exercise protocol in 3-month-old Snell dwarf mice and control littermates. Nontrained Snell dwarf gastrocnemius muscles exhibited a 1.3-fold greater muscle mass to body weight ratio than control values although muscle quality, maximum isometric torque normalized to muscle mass, and fatigue recovery were compromised. For control mice, training increased isometric torque (17%) without altering muscle mass. For Snell dwarf mice, isometric torque was unaltered by training despite decreased muscle mass that rendered muscle mass to body weight ratio comparable to control values. Muscle quality and fatigue recovery improved twofold and threefold, respectively, for Snell dwarf mice. This accompanied a fourfold increase in levels of vascular cell adhesion molecule-1 (VCAM-1), a mediator of progenitor cell recruitment, and muscle remodeling in the form of increased number of central nuclei, additional muscle fibers per unit area, and altered fiber type distribution. These results reveal a trade-off between muscle quality and longevity in the context of anterior pituitary hormone deficiency and that resistance-type training can diminish this trade-off by improving muscle quality concomitant with VCAM-1 upregulation and muscle remodeling.

Utilization of high-intensity resistance training to counter age-related sarcopenia is currently debated because of the potential for maladaptation when training design is inappropriate. Training design is problematic because the influence of various loading variables (e.g. contraction mode, repetition number, and training frequency) is still not well characterized at old age. To address this in a precisely controlled manner, we developed a rodent model of high-intensity training consisting of maximally-activated stretch-shortening contractions (SSCs), contractions typical during resistance training. With this model, we determined that at old age, high-repetition SSC training (80 SSCs: 8 sets of 10 repetitions) performed frequently (i.e. 3days per week) for 4.5weeks induced strength deficits with no muscle mass gain while decreasing frequency to 2days per week promoted increases in muscle mass and muscle quality (i.e. performance normalized to muscle mass). This finding confirmed the popular notion that decreasing training frequency has a robust effect with age. Meanwhile, the influence of other loading variables remains contentious. The aim of the present study was to assess muscle adaptation following modulation of contraction mode and repetition number during high-intensity SSC training. Muscles of young (3month old) and old (30month old) male rats were exposed to 4.5weeks of low-repetition static training of 4 (i.e. 4 sets of one repetition) isometric (ISO) contractions 3days per week or a more moderate-repetition dynamic training of 40 SSCs (i.e. 4 sets of 10 repetitions) 3days per week. For young rats, performance and muscle mass increased regardless of training protocol. For old rats, no muscle mass adaptation was observed for 4 ISO training while 40 SSC training induced muscle mass gain without improvement in muscle quality, an outcome distinct from modulating training frequency. Muscle mass gain for old rats was accompanied by decreased protein levels of tumor necrosis factor alpha, a mediator of age-related chronic inflammatory signaling, to young levels. These findings suggest that while dynamic high-intensity training with a moderate number of repetitions has a limited capacity for altering muscle quality, such training is a viable strategy for countering age-related inflammatory signaling and modifying muscle mass.

With aging, muscle injury from rapid, continuous stretch-shortening contractions (SSCs) is prolonged and maladaptation to moderate-velocity, intermittent SSCs is more common. We investigate the hypothesis that high baseline levels of inflammatory signaling and oxidative stress may underlie these outcomes, while careful modulation of high-intensity SSC training design resets basal conditions and permits muscle adaptation to SSCs.

BACKGROUND: The vast majority of dynamometer-based animal models for investigation of the response to chronic muscle contraction exposure has been limited to analysis of isometric, lengthening, or shortening contractions in isolation. An exception to this has been the utilization of a rat model to study stretch-shortening contractions (SSCs), a sequence of consecutive isometric, lengthening, and shortening contractions common during daily activity and resistance-type exercise. However, the availability of diverse genetic strains of rats is limited. Therefore, the purpose of the present study was to develop a dynamometer-based SSC training protocol to induce increased muscle mass and performance in plantarflexor muscles of mice. METHODS: Young (3 months old) C57BL/6 mice were subjected to 1 month of plantarflexion SSC training. Hindlimb muscles were analyzed for muscle mass, quantitative morphology, myogenesis/myopathy relevant gene expression, and fiber type distribution. RESULTS: The main aim of the research was achieved when training induced a 2-fold increase in plantarflexion peak torque output and a 19% increase in muscle mass for the agonist plantaris (PLT) muscle. In establishing this model, several outcomes emerged which raised the value of the model past that of being a mere recapitulation of the rat model. An increase in the number of muscle fibers per transverse muscle section accounted for the PLT muscle mass gain while the antagonist tibialis anterior (TA) muscle atrophied by 30% with preferential atrophy of type IIb and IIx fibers. These alterations were accompanied by distinct gene expression profiles. CONCLUSIONS: The findings confirm the development of a stretch-shortening contraction training model for the PLT muscle of mice and demonstrate that increased cross-sectional fiber number can occur following high-intensity SSC training. Furthermore, the TA muscle atrophy provides direct evidence for the concept of muscle imbalance in phasic non-weight bearing muscles, a concept largely characterized based on clinical observation of patients. The susceptibility to this imbalance is demonstrated to be selective for the type IIb and IIx muscle fiber types. Overall, the study highlights the importance of considering muscle fiber number modulation and the effect of training on surrounding muscles in exercise comprised of SSCs.

Exercise is the most accessible, efficacious, and multifactoral intervention to improve health and treat chronic disease. High-intensity resistance exercise, in particular, also maximizes skeletal muscle size and strength - outcomes crucial at advanced age. However, such training is capable of inducing muscle maladaptation when misapplied at old age. Therefore, characterization of parameters (e.g. mode and frequency) which foster adaptation is an active research area. To address this issue, we utilized a rodent model that allowed training at maximal intensity in terms of muscle activation and tested the hypothesis that muscles of old rats adapt to stretch-shortening contraction training, provided the training frequency is sufficiently low. At termination of training, normalized muscle mass (i.e. muscle mass divided by tibia length) and muscle quality (isometric force divided by normalized muscle mass) were determined. For young rats, normalized muscle mass increased by ~20% regardless of training frequency. No difference was also observed for muscle quality values after 2 days vs 3 days per week training (0.65 +/- 0.09 N/mg/mm vs 0.59 +/- 0.05 N/mg/mm, respectively). For old rats following 3 days per week training, normalized muscle mass was unaltered and muscle quality was 30% lower than young levels. Following 2 days per week training at old age, normalized muscle mass increased by 17% and muscle quality was restored to young levels. To investigate this enhanced response, oxidative stress was assessed by lipid peroxidation quantification. For young rats, lipid peroxidation levels were unaltered by training. With aging, baseline levels of lipid peroxidation increased by 1.5-fold. For old rats, only 2 days per week training decreased lipid peroxidation to levels indistinguishable from young values. These results imply appropriately scheduled high-intensity stretch-shortening contraction training at old age is capable of restoring muscle to a younger phenotype in terms of lipid peroxidation levels and muscle quality.

Age-related differences in contraction-induced adaptation have been well characterized especially for young and old rodent models but much less so at intermediate ages. Therefore, additional research is warranted to determine to what extent alterations in adaptation are due to maturation versus aging per se. The purpose of our study was to evaluate muscles of Fisher 344XBrown Norway rats of various ages following one month of exposure to stretch-shortening contractions (SSCs). With exposure, muscles mass increased by ~10% for 27 and 30 month old rats vs. ~20% for 3 and 6 month old rats (P < 0.05). For 3 month old rats, maximum isometric force and dynamic peak force increased by 22 +/- 8% and 27 +/- 10%, respectively (P < 0.05). For 6 month old rats, these forces were unaltered by exposure and positive work capacity diminished by 27 +/- 2% (P = 0.006). By 30 months of age, age-related deficits in maximum isometric force, peak force, negative work, and positive work were apparent and SSC exposure was ineffective at counteracting such deficits. Recovery from fatigue was also tested and exposure-induced improvements in fatigue recovery were indicated for 6 month old rats and to a lesser extent for 3 month old rats whereas no such effect was observed for older rats. Alterations in fatigue recovery were accompanied by evidence of substantial type IIb to IIx fiber type shifting. These results highlight the exceptional adaptive capacity for strength at a young age, the inclination for adaptation in fatigue recovery at early adulthood, and diminished adaptation for muscle performance in general beginning at late adulthood. Such findings motivate careful investigation to determine appropriate SSC exposures at all stages of life.

Recovery from contraction-induced injury is impaired with aging. At a young age, the secondary response several days following contraction-induced injury consists of edema, inflammatory cell infiltration, and segmental muscle fiber degeneration to aid in the clearance of damaged tissue and repair. This morphological response has not been wholly established at advanced age. Our aim was to characterize muscle fiber morphology 3 and 10days following stretch-shortening contractions (SSCs) varying in repetition number (i.e. 0, 30, 80, and 150) for young and old rats. For muscles of young rats, muscle fiber degeneration was overt at 3days exclusively after 80 or 150 SSCs and returned significantly closer to control values by 10days. For muscles of old rats, no such responses were observed. Transcriptional microarray analysis at 3days demonstrated that muscles of young rats differentially expressed up to 2144 genes while muscles of old rats differentially expressed 47 genes. Bioinformatic analysis indicated that cellular movement was a major biological process over-represented with genes that were significantly altered by SSCs especially for young rats. Protein levels in muscle for various cytokines and chemokines, key inflammatory factors for cell movement, increased 3- to 50-fold following high-repetition SSCs for young rats with no change for old rats. This age-related differential response was insightful given that for control (i.e. 0 SSCs) conditions, protein levels of circulatory cytokines/chemokines were increased with age. The results demonstrate ongoing systemic low-grade inflammatory signaling and subsequent desensitization of the cytokine/chemokine and morphological response to contraction-induced injury with aging - features which accompany age-related impairment in muscle recovery.

Investigation of volitional animal models of resistance training has been instrumental in our understanding of adaptive training. However, these studies have lacked reactive force measurements, a precise performance measure, and morphological analysis at a distinct phase of training - when initial strength gains precede muscle hypertrophy. Our aim was to expose rats to one month of training (70 or 700 g load) on a custom-designed weight-lifting apparatus for analysis of reactive forces and muscle morphology prior to muscle hypertrophy. Exclusively following 700 g load training, forces increased by 21% whereas muscle masses remained unaltered. For soleus (SOL) and tibialis anterior (TA) muscles, 700 g load training increased muscle fiber number per unit area by approximately 20% and decreased muscle fiber area by approximately 20%. Additionally, number of muscle fibers per section increased by 18% for SOL muscles. These results establish that distinct morphological alterations accompany early strength gains in a volitional animal model of load-dependent adaptive resistance training.