Identifying evidence-practice gaps for shoulder injury risk factors in competitive swimmers: uniting literature and expert opinion.

OBJECTIVES: To identify evidence-practice gaps regarding shoulder injury risk factors in competitive swimmers. METHODS: We gathered insights from 27 swimming experts including elite swimmers, coaches, high-performance staff and applied researchers using Concept Mapping. Participants brainstormed, sorted and rated (from 1 (least) to 10 (most) important and modifiable) their ideas of shoulder injury risk factors in competitive swimmers. Proposed risk factors rated above the grand mean for importance (6.2±0.4) or modifiability (6.5±0.5) ratings were considered highly important/modifiable. Expert opinions were then juxtaposed with systematic review findings to identify overlaps or convergences. RESULTS: Brainstorming generated 126 proposed shoulder injury risk factors for competitive swimmers, subsequently refined to 61 unique proposed risk factors by removing duplicates and combining similar responses. The participants sorted the 61 risk factors into seven distinct clusters. Experts perceived 36/61 proposed risk factors as highly important, of which 6 were supported by literature, 6 showed no association with injury, 2 had conflicting evidence and the remaining 22 have not yet been investigated, suggesting an evidence-practice gap. Three proposed risk factors 'inconsistent training load', 'poor stroke technique' and 'low posterior shoulder strength-endurance' exhibited high perceived importance, high perceived modifiability and supporting evidence. CONCLUSION: An evidence-practice gap was identified for 28 proposed risk factors perceived as highly important by swimming experts despite either (1) no relevant empirical research (n=22), or (2) no association with injury (n=6) from synthesised evidence. Greater collaboration between researchers and practitioners is needed to effectively address shoulder injury risk factors in competitive swimmers.

Disuse-induced muscle fibrosis, cellular senescence, and senescence-associated secretory phenotype in older adults are alleviated during re-ambulation with metformin pre-treatment.

Muscle inflammation and fibrosis underlie disuse-related complications and may contribute to impaired muscle recovery in aging. Cellular senescence is an emerging link between inflammation, extracellular matrix (ECM) remodeling and poor muscle recovery after disuse. In rodents, metformin has been shown to prevent cellular senescence/senescent associated secretory phenotype (SASP), inflammation, and fibrosis making it a potentially practical therapeutic solution. Thus, the purpose of this study was to determine in older adults if metformin monotherapy during bed rest could reduce muscle fibrosis and cellular senescence/SASP during the re-ambulation period. A two-arm controlled trial was utilized in healthy male and female older adults (n = 20; BMI: <30, age: 60 years+) randomized into either placebo or metformin treatment during a two-week run-in and 5 days of bedrest followed by metformin withdrawal during 7 days of recovery. We found that metformin-treated individuals had less type-I myofiber atrophy during disuse, reduced pro-inflammatory transcriptional profiles, and lower muscle collagen deposition during recovery. Collagen content and myofiber size corresponded to reduced whole muscle cellular senescence and SASP markers. Moreover, metformin treatment reduced primary muscle resident fibro-adipogenic progenitors (FAPs) senescent markers and promoted a shift in fibroblast fate to be less myofibroblast-like. Together, these results suggest that metformin pre-treatment improved ECM remodeling after disuse in older adults by possibly altering cellular senescence and SASP in skeletal muscle and in FAPs.

Shoulder pain and injury risk factors in competitive swimmers: A systematic review.

AIM: To synthesize and assess the literature for shoulder pain and injury risk factors in competitive swimmers. DESIGN: Systematic review with best-evidence synthesis. DATA SOURCES: CINHAL, SportDiscus, Scorpus, PubMed, and Embase databases from 1966 to April 30 2022. SEARCH AND INCLUSION: Cohort, cross-sectional, and case-control studies investigating shoulder pain or injury risk factors in competitive swimmers were included. Quality of eligible studies were assessed using a modified Newcastle-Ottawa scale. Risk factors were divided into four categories: modifiable-intrinsic, modifiable-extrinsic, non-modifiable, and other/secondary. RESULTS: Of 1356 studies identified, 24 full texts were evaluated for methodological quality, 22 met the criteria and were included in best evidence synthesis. There was no strong evidence supporting or refuting the association between 80 assessed variables and shoulder injury or pain. The swimmers' competitive level (nondirectional), and shoulder muscle recruitment profiles (e.g., increased activity of serratus anterior) exhibited moderate evidence supporting an association. Conversely, internal and external range of motion, middle finger back scratch test, training frequency, specialty stroke, height/weight, sex, and age all had moderate evidence opposing an association. Limited evidence was found for 58 variables, and conflicting for 8. The highest quality study (n = 201) suggested high acute-to-chronic workload ratio and reduced posterior shoulder strength endurance are associated with injury. CONCLUSIONS: Due to the paucity of high-quality studies, future prospective studies are needed to reevaluate known risk factor associations over exploring additional potential risk factors. Swimming practitioners should be aware of the nondirectional association of a swimmer's competitive level and pain, as squad changes could impact injury incidence. Moreover, swimmers experiencing shoulder pain may show increased activity in shoulder stabilizers during specific movements. Importantly, shoulder strength-endurance may be the most clinically relevant modifiable intrinsic risk factor.

Global deletion of CCL2 has adverse impacts on recovery of skeletal muscle fiber size and function and is muscle specific.

Timely and complete recovery of muscle mass and function following a bout of physical disuse are critical components of returning to normal activities of daily living and lifestyle. Proper cross talk between the muscle tissue and myeloid cells (e.g., macrophages) throughout the recovery period from disuse atrophy plays a significant role in the complete resolution of muscle size and function. Chemokine C-C motif ligand 2 (CCL2) has a critical function of recruiting macrophages during the early phase of muscle damage. However, the importance of CCL2 has not been defined in the context of disuse and recovery. Here, we utilized a mouse model of whole body CCL2 deletion (CCL2KO) and subjected them to a period of hindlimb unloading followed by reloading to investigate the importance of CCL2 on the regrowth of muscle following disuse atrophy using ex vivo muscle tests, immunohistochemistry, and fluorescence-activated cell sorting approaches. We show mice that lack CCL2 display an incomplete recovery of gastrocnemius muscle mass, myofiber cross-sectional area, and EDL muscle contractile characteristics during the recovery from disuse atrophy. The soleus and plantaris had limited impact as a result of CCL2 deficiency suggesting a muscle-specific effect. Mice that lack CCL2 have decreased skeletal muscle collagen turnover, which may be related to defects in muscle function and stiffness. In addition, we show that the recruitment of macrophages to gastrocnemius muscle was dramatically reduced in CCL2KO mice during the recovery from disuse atrophy, which likely precipitated poor recovery of muscle size and function and aberrant collagen remodeling.NEW & NOTEWORTHY We provide evidence that the whole body loss of CCL2 in mice has adverse impacts on whole body function and skeletal muscle-specific contractile characteristics and collagen content. These defects in muscle function worsened during the recovery from disuse atrophy and corresponded with decreased recovery of muscle mass. We conclude that the absence of CCL2 decreased recruitment of proinflammatory macrophages to the muscle during the regrowth phase following disuse atrophy resulting in impaired collagen remodeling events and full resolution of muscle morphology and function.

Pharmacological modulation of adrenergic tone alters the vasodilatory response to passive leg movement in young but not in old adults.

The age-related increase in α-adrenergic tone may contribute to decreased leg vascular conductance (LVC) both at rest and during exercise in the old. However, the effect on passive leg movement (PLM)-induced LVC, a measure of vascular function, which is markedly attenuated in this population, is unknown. Thus, in eight young (25 ± 5 yr) and seven old (65 ± 7 yr) subjects, this investigation examined the impact of systemic ß-adrenergic blockade (propanalol, PROP) alone, and PROP combined with either α1-adrenergic stimulation (phenylephrine, PE) or α-adrenergic inhibition (phentolamine, PHEN), on PLM-induced vasodilation. LVC, calculated from femoral artery blood flow and pressure, was determined and PLM-induced Δ peak (LVCΔpeak) and total vasodilation (LVCAUC, area under curve) were documented. PROP decreased LVCΔpeak (PROP: 4.8 ± 1.8, Saline: 7.7 ± 2.7 mL·mmHg-1, P < 0.001) and LVCAUC (PROP: 1.1 ± 0.7, Saline: 2.4 ± 1.6 mL·mmHg-1, P = 0.002) in the young, but not in the old (LVCΔpeak, P = 0.931; LVCAUC, P = 0.999). PE reduced baseline LVC (PE: 1.6 ± 0.4, PROP: 2.3 ± 0.4 mL·min-1·mmHg-1, P < 0.01), LVCΔpeak (PE: 3.2 ± 1.3, PROP: 4.8 ± 1.8 mL·min-1·mmHg-1, P = 0.004), and LVCAUC (PE: 0.5 ± 0.4, PROP: 1.1 ± 0.7 mL·mmHg-1, P = 0.011) in the young, but not in the old (baseline LVC, P = 0.199; LVCΔpeak, P = 0.904; LVCAUC, P = 0.823). PHEN increased LVC at rest and throughout PLM in both groups (drug effect: P < 0.05), however LVCΔpeak was only improved in the young (PHEN: 6.4 ± 3.1, PROP: 4.4 ± 1.5 mL·min-1·mmHg-1, P = 0.004), and not in the old (P = 0.904). Furthermore, the magnitude of α-adrenergic modulation (PHEN - PE) of LVCΔpeak was greater in the young compared with the old (Young: 3.35 ± 2.32, Old: 0.40 ± 1.59 mL·min-1·mmHg-1, P = 0.019). Therefore, elevated α-adrenergic tone does not appear to contribute to the attenuated vascular function with age identified by PLM.NEW & NOTEWORTHY Stimulation of α1-adrenergic receptors eliminated age-related differences in passive leg movement (PLM) by decreasing PLM-induced vasodilation in the young. Systemic ß-blockade attenuated the central hemodynamic component of the PLM response in young individuals. Inhibition of α-adrenergic receptors did not improve the PLM response in older individuals, though withdrawal of α-adrenergic modulation augmented baseline and maximal vasodilation in both groups. Accordingly, α-adrenergic signaling plays a role in modulating the PLM vasodilatory response in young but not in old adults, and elevated α-adrenergic tone does not appear to contribute to the attenuated vascular function with age identified by PLM.

Muscle disuse as hindlimb unloading in early postnatal mice negatively impacts grip strength in adult mice: a pilot study.

Physical inactivity has many detrimental effects on health, yet the impact of physical inactivity in early life on muscle health in adulthood remains unknown. Early postnatal malnutrition has prolonged effects into adulthood and we propose that early postnatal (P) physical inactivity would have similar negative effects. To test this hypothesis, we exposed postnatal mice (∼P28, C57BL/6J) to 14 days of physical inactivity (shortly after weaning, from ∼P28 to P42 days of age) in the form of muscle disuse with hindlimb unloading (HU). After this early-life physical inactivity, they were allowed to normally ambulate until 5 mo of age (P140, adulthood) when they underwent 14 days of HU with and without 7-day recovery. They were then tested for physical function (grip strength) and muscles were extracted and weighed. Immunofluorescence was carried out on these muscle cross sections for analysis of myofiber cross-sectional area (fCSA), macrophage density (CD68+ cells), and extracellular matrix (ECM) area. Muscle weights and fCSA and myofiber diameter were used to quantify changes in muscle and fiber size. Compared with age-matched controls, no notable effects of early-life physical inactivity (HU) on skeletal muscle and myofiber size were observed. However, a significant reduction in adult grip strength was observed in those exposed to HU early in life. This was associated with reduced muscle macrophages and increased ECM area. Exposure to a short period of early life disuse has negative enduring effects into adulthood impacting grip strength, muscle macrophages, and muscle composition as low muscle quality.NEW & NOTEWORTHY We demonstrate that early life disuse resulted in less grip strength in adulthood. Analysis of muscle composition demonstrated no loss of whole muscle or myofiber size indicating lower muscle quality akin to premature aging. This poor muscle quality was characterized by altered muscle macrophages and extracellular matrix area. We demonstrate intriguing correlations between this loss of grip strength and muscle macrophages and also area of noncontractile tissue in the muscle.

Fatigue Increases Muscle Activations but Does Not Change Maximal Joint Angles during the Bar Dip.

The purpose of this study was to profile and compare the bar dip's kinematics and muscle activation patterns in non-fatigued and fatigued conditions. Fifteen healthy males completed one set of bar dips to exhaustion. Upper limb and trunk kinematics, using 3D motion capture, and muscle activation intensities of nine muscles, using surface electromyography, were recorded. The average kinematics and muscle activations of repetitions 2-4 were considered the non-fatigued condition, and the average of the final three repetitions was considered the fatigued condition. Paired t-tests were used to compare kinematics and muscle activation between conditions. Fatigue caused a significant increase in repetition duration (p < 0.001) and shifted the bottom position to a significantly earlier percentage of the repetition (p < 0.001). There were no significant changes in the peak joint angles measured. However, there were significant changes in body position at the top of the movement. Fatigue also caused an increase in peak activation amplitude in two agonist muscles (pectoralis major [p < 0.001], triceps brachii [p < 0.001]), and three stabilizer muscles. For practitioners prescribing the bar dip, fatigue did not cause drastic alterations in movement technique and appears to target pectoralis major and triceps brachii effectively.

Bench, Bar, and Ring Dips: Do Kinematics and Muscle Activity Differ?

The purpose of this study was to profile and compare the kinematics, using 3D motion capture, and muscle activation patterns, using surface electromyography (sEMG), of three common dip variations; the bench, bar, and ring dips. Thirteen experienced males performed four repetitions of each dip variation. For each participant, repetitions 2-4 were time-normalized and then averaged to produce a mean value for all kinematic and sEMG variables. The mean maximal joint angles and mean peak sEMG amplitudes were compared between each variation using a one-way ANOVA with repeated measures. Several significant differences (p < 0.05) between dip variations were observed in both kinematic and sEMG data. The bench dip predominantly targets the triceps brachii but requires greater shoulder extension range. The mean peak triceps brachii activation was 0.83 ± 0.34 mV on the bench, 1.04 ± 0.27 mV on the bar, and 1.05 ± 0.40 mV on the ring. The bar dip is an appropriate progression from the bench dip due to the higher peak muscle activations. The ring dip had similar peak activations to the bar dip, with three muscles increasing their activation intensities further. These findings have implications for practitioners prescribing the dip, particularly to exercisers with a history of shoulder pain and injury.

Short-term exposure to a clinical dose of metformin increases skeletal muscle mitochondrial H2O2 emission and production in healthy, older adults: A randomized controlled trial.

BACKGROUND AND AIMS: Metformin is the most commonly prescribed medication to treat diabetes. Emerging evidence suggests that metformin could have off target effects that might help promote healthy muscle aging, but these effects have not been thoroughly studied in glucose tolerant older individuals. The purpose of this study was to investigate the short-term effects of metformin consumption on skeletal muscle mitochondrial bioenergetics in healthy older adults. METHODS: We obtained muscle biopsy samples from 16 healthy older adults previously naïve to metformin and treated with metformin (METF; 3F, 5M), or placebo (CON; 3F, 5M), for two weeks using a randomized and blinded study design. Samples were analyzed using high-resolution respirometry, immunofluorescence, and immunoblotting to assess muscle mitochondrial bioenergetics, satellite cell (SC) content, and associated protein markers. RESULTS: We found that metformin treatment did not alter maximal mitochondrial respiration rates in muscle compared to CON. In contrast, mitochondrial H2O2 emission and production were elevated in muscle samples from METF versus CON (METF emission: 2.59 ± 0.72 SE Fold, P = 0.04; METF production: 2.29 ± 0.53 SE Fold, P = 0.02). Furthermore, the change in H2O2 emission was positively correlated with the change in type 1 myofiber SC content and this was biased in METF participants (Pooled: R2 = 0.5816, P = 0.0006; METF: R2 = 0.674, P = 0.0125). CONCLUSIONS: These findings suggest that acute exposure to metformin does not impact mitochondrial respiration in aged, glucose-tolerant muscle, but rather, influences mitochondrial-free radical and SC dynamics. CLINICAL TRIAL REGISTRATION: NCT03107884, clinicaltrials.gov.

Cardiovasomobility: an integrative understanding of how disuse impacts cardiovascular and skeletal muscle health.

Cardiovasomobility is a novel concept that encompasses the integration of cardiovascular and skeletal muscle function in health and disease with critical modification by physical activity, or lack thereof. Compelling evidence indicates that physical activity improves health while a sedentary, or inactive, lifestyle accelerates cardiovascular and skeletal muscle dysfunction and hastens disease progression. Identifying causative factors for vascular and skeletal muscle dysfunction, especially in humans, has proven difficult due to the limitations associated with cross-sectional investigations. Therefore, experimental models of physical inactivity and disuse, which mimic hospitalization, injury, and illness, provide important insight into the mechanisms and consequences of vascular and skeletal muscle dysfunction. This review provides an overview of the experimental models of disuse and inactivity and focuses on the integrated responses of the vasculature and skeletal muscle in response to disuse/inactivity. The time course and magnitude of dysfunction evoked by various models of disuse/inactivity are discussed in detail, and evidence in support of the critical roles of mitochondrial function and oxidative stress are presented. Lastly, strategies aimed at preserving vascular and skeletal muscle dysfunction during disuse/inactivity are reviewed. Within the context of cardiovasomobility, experimental manipulation of physical activity provides valuable insight into the mechanisms responsible for vascular and skeletal muscle dysfunction that limit mobility, degrade quality of life, and hasten the onset of disease.

Metformin and leucine increase satellite cells and collagen remodeling during disuse and recovery in aged muscle.

Loss of muscle mass and strength after disuse followed by impaired muscle recovery commonly occurs with aging. Metformin (MET) and leucine (LEU) individually have shown positive effects in skeletal muscle during atrophy conditions but have not been evaluated in combination nor tested as a remedy to enhance muscle recovery following disuse atrophy in aging. The purpose of this study was to determine if a dual treatment of metformin and leucine (MET + LEU) would prevent disuse-induced atrophy and/or promote muscle recovery in aged mice and if these muscle responses correspond to changes in satellite cells and collagen remodeling. Aged mice (22-24 months) underwent 14 days of hindlimb unloading (HU) followed by 7 or 14 days of reloading (7 or 14 days RL). MET, LEU, or MET + LEU was administered via drinking water and were compared to Vehicle (standard drinking water) and ambulatory baseline. We observed that during HU, MET + LEU resolved whole body grip strength and soleus muscle specific force decrements caused by HU. Gastrocnemius satellite cell abundance was increased with MET + LEU treatment but did not alter muscle size during disuse or recovery conditions. Moreover, MET + LEU treatment alleviated gastrocnemius collagen accumulation caused by HU and increased collagen turnover during 7 and 14 days RL driven by a decrease in collagen IV content. Transcriptional pathway analysis revealed that MET + LEU altered muscle hallmark pathways related to inflammation and myogenesis during HU. Together, the dual treatment of MET and LEU was able to increase muscle function, satellite cell content, and reduce collagen accumulation, thus improving muscle quality during disuse and recovery in aging.

Disrupted macrophage metabolic reprogramming in aged soleus muscle during early recovery following disuse atrophy.

Aged skeletal muscle is characterized by poor muscle recovery following disuse coinciding with an impaired muscle pro-inflammatory macrophage response. Macrophage inflammatory status is regulated by its metabolic state, but little is understood of macrophage metabolism and its relation to macrophage inflammation in the context of muscle recovery and aging. Therefore, the purpose of this study was to thoroughly characterize macrophage metabolism and inflammation in aged muscle during early recovery following disuse atrophy using single cell transcriptomics and functional assays. Young (4-5 months) and old (20-22 months) male C57BL/6 mice underwent 14 days of hindlimb unloading followed by 4 days of ambulatory recovery. CD45+ cells were isolated from solei muscles and analyzed using 10x Genomics single cell RNA sequencing. We found that aged pro-inflammatory macrophage clusters were characterized with an impaired inflammatory and glycolytic transcriptome, and this dysregulation was accompanied by a suppression of HIF-1α and its immediate downstream target, Glut1. As a follow-up, bone marrow-derived macrophages were isolated from a separate cohort of young and old mice at 4-d recovery and were polarized to a pro-inflammatory phenotype and used for glycolysis stress test, phagocytosis activity assay, and targeted GC-MS metabolomics. Aged bone marrow-derived pro-inflammatory macrophages were characterized with impaired glycolysis and phagocytosis function, decreased succinate and an accumulation of glycolytic metabolic intermediates overall supporting reduced glycolytic flux and macrophage function. Our results indicate that the metabolic reprograming and function of aged skeletal muscle pro-inflammatory macrophages are dysfunctional during early recovery from disuse atrophy possibly attributing to attenuated regrowth.

Impact of presymptomatic COVID-19 on vascular and skeletal muscle function: a case study.

The impact of COVID-19 has been largely described after symptom development. Although the SARS-CoV-2 virus elevates heart rate (HR) prior to symptom onset, whether this virus evokes other presymptomatic alterations is unknown. This case study details the presymptomatic impact of COVID-19 on vascular and skeletal muscle function in a young woman [24 yr, 173.5 cm, 89 kg, body mass index (BMI): 29.6 kg·m-2]. Vascular and skeletal muscle function were assessed as part of a separate study with the first and second visits separated by 2 wk. On the evening following the second visit, the participant developed a fever and a rapid antigen test confirmed a positive COVID-19 diagnosis. Compared with the first visit, the participant presented with a markedly elevated HR (∼30 beats/min) and a lower mean blood pressure (∼8 mmHg) at the second visit. Vascular function measured by brachial artery flow-mediated dilation, reactive hyperemia, and passive leg movement were all noticeably attenuated (25%-65%) as was leg blood flow during knee extension exercise. Muscle strength was diminished as was ADP-stimulated respiration (30%), assessed in vitro, whereas there was a 25% increase in the apparent Km. Lastly, an elevation in IL-10 was observed prior to symptom onset. Notably, 2.5 mo after diagnosis symptoms of fatigue and cough were still present. Together, these findings provide unique insight into the physiological responses immediately prior to onset of COVID-19 symptoms; they suggest that SARS-CoV-2 negatively impacts vascular and skeletal muscle function prior to the onset of common symptoms and may set the stage for the widespread sequelae observed following COVID-19 diagnosis.NEW & NOTEWORTHY This unique case study details the impact of SARS-CoV-2 infection on vascular and skeletal muscle function in a young predominantly presymptomatic woman. Prior to COVID-19 diagnosis, substantial reductions in vascular, skeletal muscle, and mitochondrial function were observed along with an elevation in IL-10. This integrative case study indicates that the presymptomatic impact of COVID-19 is widespread and may help elucidate the acute and long-term sequelae of this disease.

Reduced Physical Activity Alters the Leucine-Stimulated Translatome in Aged Skeletal Muscle.

Periods of inactivity experienced by older adults induce nutrient anabolic resistance creating a cascade of skeletal muscle transcriptional and translational aberrations contributing to muscle dysfunction. The purpose of this study was to identify how inactivity alters leucine-stimulated translation of molecules and pathways within the skeletal muscle of older adults. We performed ribosomal profiling alongside RNA sequencing from skeletal muscle biopsies taken from older adults (n = 8; ~72 years; 6 F/2 M) in response to a leucine bolus before (Active) and after (Reduced Activity) 2 weeks of reduced physical activity. At both visits, muscle biopsies were taken at baseline, 60 minutes (early response), and 180 minutes (late response) after leucine ingestion. Previously identified inactivity-related gene transcription changes (PFKFB3, GADD45A, NMRK2) were heightened by leucine with corresponding changes in translation. In contrast, leucine also stimulated translational efficiency of several transcripts in a manner not explained by corresponding changes in mRNA abundance ("uncoupled translation"). Inactivity eliminated this uncoupled translational response for several transcripts, and reduced the translation of most mRNAs encoding for ribosomal proteins. Ingenuity Pathway Analysis identified discordant circadian translation and transcription as a result of inactivity such as translation changes to PER2 and PER3 despite unchanged transcription. We demonstrate inactivity alters leucine-stimulated "uncoupled translation" of ribosomal proteins and circadian regulators otherwise not detectable by traditional RNA sequencing. Innovative techniques such as ribosomal profiling continues to further our understanding of how physical activity mediates translational regulation, and will set a path toward therapies that can restore optimal protein synthesis on the transcript-specific level to combat negative consequences of inactivity on aging muscle.

Acute Effects of Cheddar Cheese Consumption on Circulating Amino Acids and Human Skeletal Muscle.

Cheddar cheese is a protein-dense whole food and high in leucine content. However, no information is known about the acute blood amino acid kinetics and protein anabolic effects in skeletal muscle in healthy adults. Therefore, we conducted a crossover study in which men and women (n = 24; ~27 years, ~23 kg/m2) consumed cheese (20 g protein) or an isonitrogenous amount of milk. Blood and skeletal muscle biopsies were taken before and during the post absorptive period following ingestion. We evaluated circulating essential and non-essential amino acids, insulin, and free fatty acids and examined skeletal muscle anabolism by mTORC1 cellular localization, intracellular signaling, and ribosomal profiling. We found that cheese ingestion had a slower yet more sustained branched-chain amino acid circulation appearance over the postprandial period peaking at ~120 min. Cheese also modestly stimulated mTORC1 signaling and increased membrane localization. Using ribosomal profiling we found that, though both milk and cheese stimulated a muscle anabolic program associated with mTORC1 signaling that was more evident with milk, mTORC1 signaling persisted with cheese while also inducing a lower insulinogenic response. We conclude that Cheddar cheese induced a sustained blood amino acid and moderate muscle mTORC1 response yet had a lower glycemic profile compared to milk.

Short-term metformin ingestion by healthy older adults improves myoblast function.

Muscle progenitor cells (MPCs) in aged muscle exhibit impaired activation into proliferating myoblasts, thereby impairing fusion and changes in secreted factors. The antihyperglycemic drug metformin, currently studied as a candidate antiaging therapy, may have potential to promote function of aged MPCs. We evaluated the impact of 2 wk of metformin ingestion on primary myoblast function measured in vitro after being extracted from muscle biopsies of older adult participants. MPCs were isolated from muscle biopsies of community-dwelling older (4 male/4 female, ∼69 yr) adult participants before (pre) and after (post) the metformin ingestion period and studied in vitro. Cells were extracted from Young participants (4 male/4 female, ∼27 yr) to serve as a "youthful" comparator. MPCs from Old subjects had lower fusion index and myoblast-endothelial cell homing compared with Young, while Old MPCs, extracted after short-term metformin ingestion, performed better at both tasks. Transcriptomic analyses of Old MPCs (vs. Young) revealed decreased histone expression and increased myogenic pathway activity, yet this phenotype was partially restored by metformin. However, metformin ingestion exacerbated pathways related to inflammation signaling. Together, this study demonstrated that 2 wk of metformin ingestion induced persistent effects on Old MPCs that improved function in vitro and altered their transcriptional signature including histone and chromatin remodeling.