Age-associated chronic basal inflammation compromises muscle mass and adaptability, but exercise training may exert an anti-inflammatory effect. This investigation assessed basal and exercise-induced ...inflammation in three cohorts of men: young exercisers YE;
= 10 men; 25 ± 1 yr; maximal oxygen consumption (V̇o
), 53 ± 3 mL·kg
·min
; quadriceps area, 78 ± 3 cm
; means ± SE, old healthy nonexercisers (OH;
= 10; 75 ± 1 yr; V̇o
, 22 ± 1 mL·kg
·min
; quadriceps area, 56 ± 3 cm
), and lifelong exercisers with an aerobic training history of 53 ± 1 yr (LLE;
= 21; 74 ± 1 yr; V̇o
, 34 ± 1 mL·kg
·min
; quadriceps area, 67 ± 2 cm
). Resting serum IL-6, TNF-α, C-reactive protein, and IGF-1 levels were measured. Vastus lateralis muscle biopsies were obtained at rest (basal) and 4 h after an acute exercise challenge (3 × 10 repetitions, 70% 1-repetition maximum) to assess gene expression of cytokines IL-6, TNF-α, IL-1β, IL-10, IL-4, interleukin-1 receptor antagonist (IL-1Ra), and transforming growth factor-β (TGF-β), chemokines IL-8 and monocyte chemoattractant protein-1 (MCP-1), cyclooxygenase enzymes cyclooxygenase-1 and -2 (COX-1 and COX-2, respectively), prostaglandin E
synthases microsomal prostaglandin E synthase 1 (mPGES-1) and cytosolic prostaglandin E
synthase (cPGES) and receptors prostaglandin E
receptor EP3 and EP4 subtypes (EP3 and EP4, respectively), and macrophage markers cluster of differentiation 16b (CD16b) and CD163, as well as basal macrophage abundance (CD68
cells). Aging led to higher (
≤ 0.05) circulating IL-6 and skeletal muscle COX-1, mPGES-1, and CD163 expression. However, LLE had significantly lower serum IL-6 levels (
≤ 0.05 vs. OH) and a predominantly anti-inflammatory muscle profile higher IL-10 (
≤ 0.05 vs. YE), TNF-α, TGF-β, and EP4 levels (
≤ 0.05 vs. OH). In OH only, acute exercise increased expression of proinflammatory factors TNF-α, TGF-β, and IL-8 (
≤ 0.05). LLE had postexercise gene expression similar to YE, except lower IL-10 (
≤ 0.10), mPGES-1, and EP3 expression (
≤ 0.05). Thus, although aging led to a proinflammatory profile within blood and muscle, lifelong exercise partially prevented this and generally preserved the acute inflammatory response to exercise seen in young exercising men. Lifelong exercise may positively impact muscle health throughout aging by promoting anti-inflammation in skeletal muscle.
This study assessed a unique population of lifelong aerobic exercising men and demonstrated that their activity status exerts an anti-inflammatory effect in skeletal muscle and circulation. Furthermore, we provide evidence that the inflammatory response to acute exercise is dysregulated by aging but preserved with lifelong exercise, which might improve skeletal muscle resilience to unaccustomed loading and adaptability into late life.
Older adults undergoing age-related decrements in muscle health can benefit substantially from resistance exercise training, a potent stimulus for whole muscle and myofiber hypertrophy, neuromuscular ...performance gains, and improved functional mobility. With the use of advancing technologies, research continues to elucidate the mechanisms of and heterogeneity in adaptations to resistance exercise training beyond differences in exercise prescription. This review highlights the current knowledge in these areas and emphasizes knowledge gaps that require future attention of the field.
Low muscle mass and frailty are especially prevalent in older women and may be accelerated by age-related inflammation. Habitual physical activity throughout the life span (lifelong exercise) may ...prevent muscle inflammation and associated pathologies, but this is unexplored in women. This investigation assessed basal and acute exercise-induced inflammation in three cohorts of women: young exercisers (YE,
= 10, 25 ± 1 yr, Formula: see text: 44 ± 2 mL/kg/min, quadriceps size: 59 ± 2 cm
), old healthy nonexercisers (OH,
= 10, 75 ± 1 yr, Formula: see text: 18 ± 1 mL/kg/min, quadriceps size: 40 ± 1 cm
), and lifelong aerobic exercisers with a 48 ± 2 yr aerobic training history (LLE,
= 7, 72 ± 2 yr, Formula: see text: 26 ± 2 mL/kg/min, quadriceps size: 42 ± 2 cm
). Resting serum IL-6, TNF-α, C-reactive protein (CRP), and IGF-1 were measured. Vastus lateralis muscle biopsies were obtained at rest (basal) and 4 h after an acute exercise challenge (3 × 10 reps, 70% 1-repetition maximum) to assess gene expression of cytokines (IL-6, TNF-α, IL-1β, IL-10, IL-4, IL-1Ra, TGF-β), chemokines (IL-8, MCP-1), cyclooxygenase enzymes (COX-1, COX-2), prostaglandin E
synthases (mPGES-1, cPGES) and receptors (EP3-4), and macrophage markers (CD16b, CD163), as well as basal macrophage abundance (CD68
cells). The older cohorts (LLE + OH combined) demonstrated higher muscle IL-6 and COX-1 (
≤ 0.05) than YE, whereas LLE expressed lower muscle IL-1β (
≤ 0.05 vs. OH). Acute exercise increased muscle IL-6 expression in YE only, whereas the older cohorts combined had the higher postexercise expression of IL-8 and TNF-α (
≤ 0.05 vs. YE). Only LLE had increased postexercise expression of muscle IL-1β and MCP-1 (
≤ 0.05 vs. preexercise). Thus, aging in women led to mild basal and exercise-induced inflammation that was unaffected by lifelong aerobic exercise, which may have implications for long-term function and adaptability.
We previously reported a positive effect of lifelong exercise on skeletal muscle inflammation in aging men. This parallel investigation in women revealed that lifelong exercise did not protect against age-related increases in circulating or muscle inflammation and that preparedness to handle loading stress was not preserved by lifelong exercise. Further investigation is necessary to understand why lifelong aerobic exercise may not confer the same anti-inflammatory benefits in women as it does in men.
This study examined the effects of aging and lifelong aerobic exercise on innate immune system components in the skeletal muscle of healthy women in the basal state and after an unaccustomed ...resistance exercise (RE) challenge. We also made exploratory between-sex comparisons with our previous report on men. Three groups of women were studied: young exercisers (YE,
= 10, 25 ± 1 yr, V̇o
: 44 ± 2 mL/kg/min), lifelong aerobic exercisers with a 48 ± 2 yr training history (LLE,
= 7, 72 ± 2 yr, V̇o
: 26 ± 2 mL/kg/min), and old healthy nonexercisers (OH,
= 10, 75 ± 1 yr, V̇o
: 18 ± 1 mL/kg/min). Ten Toll-like receptors (TLRs)1-10, TLR adaptors (Myd88, TRIF), and NF-κB pathway components (IκBα, IKKβ) were assessed at the mRNA level in vastus lateralis biopsies before and 4 h after RE 3×10 repetitions, 70% 1-repetition maximum (1RM). Basal TLR1-10 expression was minimally influenced by age or LLE in women (TLR9 only; OH > YE, +43%,
< 0.05; OH > LLE, +30%,
< 0.10) and was on average 24% higher in women versus men. Similarly, basal adaptor expression was not influenced (
> 0.05) by age or LLE in women but was on average 26% higher (myeloid differentiation primary response 88, Myd88) and 23% lower Toll interleukin (IL)-1 receptor-containing adaptor-inducing interferon-γ, TRIF in women versus men. RE-induced changes in women, independent of the group, in TLR3, TLR4, TLR6 (∼2.1-fold,
< 0.05), Myd88 (∼1.2-fold,
< 0.10), and IκBα (∼0.3-fold,
< 0.05). Although there were some similar RE responses in men (TLR4: 2.1-fold, Myd88: 1.2-fold, IκBα: 0.4-fold), several components responded only in men to RE (TLR1, TLR8, TRIF, and IKKβ). Our findings support the sexual dimorphism of immunity, with women having greater basal skeletal muscle TLR expression and differential response to unaccustomed exercise than men.
We recently reported that aging increases basal expression of many Toll-like receptors (TLRs) in men and lifelong aerobic exercise does not prevent this effect. In addition, a resistance exercise (RE) challenge increased the expression of many TLRs. Here we show that basal TLR expression is minimally influenced by aging in women and findings support the sexual dimorphism of immunity, with women having greater basal skeletal muscle TLR expression and a differential response to unaccustomed exercise than men.
The purpose of this investigation was to evaluate the effects of aging and lifelong exercise on skeletal muscle components of the innate immune system. Additionally, the effects of an acute ...resistance exercise (RE) challenge were explored. Three groups of men were studied: young exercisers (YE:
= 10, 25 ± 1 yr; V̇o
: 53 ± 3 mL/kg/min; quadriceps size: 78 ± 3 cm
), lifelong aerobic exercisers with a 53 ± 1 yr training history (LLE;
= 21, 74 ± 1 yr; V̇o
: 34 ± 1 mL/kg/min; quadriceps size: 67 ± 2 cm
), and old healthy nonexercisers (OH:
= 10, 75 ± 1 yr; V̇o
: 22 ± 1 mL/kg/min, quadriceps size: 56 ± 3 cm
). Vastus lateralis muscle biopsies were obtained in the basal state and 4 h after RE (3 × 10 reps, 70% of 1 repetition maximum) to assess Toll-like receptors (TLR)1-10, TLR adaptors (Myd88 and TRIF), and NF-κB pathway components (IκΒα and IKKβ) mRNA expression. Basal TLR3, TLR6, and TLR7 tended to be higher (
≤ 0.10) with aging (LLE and OH combined). In general, RE increased expression of TLR1 and TLR8 (
≤ 0.10) and TLR3 and TLR4 (
< 0.05), although TLR3 did not respond in OH. Both TLR adaptors also responded to the exercise bout; these were primarily (Myd88, main effect
≤ 0.10) or exclusively (TRIF,
< 0.05) driven by the OH group. In summary, aging appears to increase basal expression of some innate immune components in human skeletal muscle, and lifelong aerobic exercise does not affect this age-related increase. An exercise challenge stimulates the expression of several TLRs, while the TLR adaptor response appears to be dysregulated with aging and maintained with lifelong exercise. Partially preserved muscle mass, coupled with a notable immunity profile, suggests lifelong exercisers are likely better prepared for a stress that challenges the immune system.
Findings from this investigation provide novel insight into the effect of aging and lifelong aerobic exercise on structural components of the innate immune system in skeletal muscle of humans. Data presented here suggest aging increases basal expression of select Toll-like receptors (TLRs), and lifelong exercise does not impact this age-related increase. Additionally, acute exercise stimulates gene expression of several TLRs, while the adaptor response is likely dysregulated with aging and maintained with lifelong exercise.
Ageing of skeletal muscle is characterized in some by muscle fiber type grouping due to denervation-reinnervation cycles, but the severity of fiber type grouping varies widely across individuals of ...the same chronological age. It remains unknown whether fiber type grouping is associated with lower muscle mass and/or reduced physical function in elderly. Therefore, we assessed the relationship between fiber type grouping and indices of muscle mass and physical function in older adults. In addition, we assessed whether fiber type grouping is affected by prolonged resistance training in older adults.
Twenty young (21 ± 2 y) and twenty older (70 ± 4 y) healthy men participated in the present study. Body composition (DXA-scan), quadriceps cross-sectional area (CT-scan) and muscle strength (1RM) were assessed at baseline (young and old) and following 12 weeks of resistance training (old only). Percutaneous skeletal muscle biopsies from the vastus lateralis were collected at baseline (young and old) and following exercise training (old only). Immunohistochemical analyses were performed to evaluate type I and type II muscle fiber distribution, size, myonuclear content and grouping.
At baseline, type II fibers were significantly (P < 0.05) smaller in older compared with young adults (5366 ± 1288 vs 6705 ± 1168 μm2). Whereas no differences were observed in type I, type II fiber grouping was significantly (P < 0.05) lower in older (18 ± 18 %) compared with young (32 ± 25 %) men. No significant correlations were observed between fiber type grouping and muscle mass or physical function. Prolonged resistance training in old men resulted in a significant increase (P < 0.05) in type II fiber size (from 5366 ± 1288 to 6165 ± 1484 μm2) with no significant changes in the proportion of type I muscle fibers found grouped.
Muscle fiber type grouping is not associated with lower body strength or muscle mass in healthy, older men. In addition, twelve weeks of resistance exercise training results in type II muscle fiber specific hypertrophy but does not affect fiber type grouping.
•Muscle fiber type grouping is as a hallmark of denervation-reinnervation cycles.•Severity of muscle fiber type grouping varies widely across aged individuals.•Lower type II grouping may precede higher type I grouping in senescent muscle.•Fiber grouping is not associated with lower strength or muscle mass in older men.•Resistance training does not affect fiber type grouping in healthy older adults.
Spinal cord injury (SCI) results in rapid muscle loss. Exogenous molecular interventions to slow muscle atrophy after SCI have been relatively ineffective and require the search for novel therapeutic ...targets. Connexin hemichannels (CxHCs) allow nonselective passage of small molecules into and out of the cell. Boldine, a CxHC-inhibiting aporphine found in the boldo tree (
), has shown promising preclinical results in slowing atrophy during sepsis and restoring muscle function in dysferlinopathy. We administered 50 mg/kg/day of boldine to spinal cord transected mice beginning 3 days post-injury. Tissue was collected 7 and 28 days post-SCI and the gastrocnemius was used for multiomics profiling. Boldine did not prevent body or muscle mass loss but attenuated SCI-induced changes in the abundance of the amino acids proline, phenylalanine, leucine and isoleucine, as well as glucose, 7 days post-SCI. SCI resulted in the differential expression of ∼7,700 and ∼2,000 genes at 7 and 28 days, respectively, compared with Sham controls. Pathway enrichment of these genes highlighted ribosome biogenesis at 7 days and translation and oxidative phosphorylation at both timepoints. Boldine altered the expression of ∼150 genes at 7 days and ∼110 genes at 28 days post-SCI. Pathway enrichment of these genes indicated a potential role for boldine in suppressing protein ubiquitination and degradation at the 7-day timepoint. Methylation analyses showed minimal differences between groups. Taken together, boldine is not an efficacious therapy to preserve body and muscle mass after complete SCI, though it attenuated some SCI-induced changes across the metabolome and transcriptome.
This is the first study to describe the multiome of skeletal muscle paralyzed by a spinal cord injury (SCI) in mice across the acute and subacute timeframe after injury. We show large-scale changes in the metabolome and transcriptome at 7 days post-injury compared with 28 days. Furthermore, we show that the alkaloid boldine was able to prevent SCI-induced changes in muscle glucose and free amino acid levels at 7 days, but not 28 days, after SCI.
The efficacy of the NASA SPRINT exercise countermeasures program for quadriceps (vastus lateralis) and triceps surae (soleus) skeletal muscle health was investigated during 70 days of simulated ...microgravity. Individuals completed 6° head-down-tilt bedrest (BR,
= 9), bedrest with resistance and aerobic exercise (BRE,
= 9), or bedrest with resistance and aerobic exercise and low-dose testosterone (BRE + T,
= 8). All groups were periodically tested for muscle (
= 9 times) and aerobic (
= 4 times) power during bedrest. In BR, surprisingly, the typical bedrest-induced decrements in vastus lateralis myofiber size and power were either blunted (myosin heavy chain, MHC I) or eliminated (MHC IIa), along with no change (
> 0.05) in %MHC distribution and blunted quadriceps atrophy. In BRE, MHC I (vastus lateralis and soleus) and IIa (vastus lateralis) contractile performance was maintained (
> 0.05) or increased (
< 0.05). Vastus lateralis hybrid fiber percentage was reduced (
< 0.05) and energy metabolism enzymes and capillarization were generally maintained (
> 0.05), while not all of these positive responses were observed in the soleus. Exercise offsets 100% of quadriceps and approximately two-thirds of soleus whole muscle mass loss. Testosterone (BRE + T) did not provide any benefit over exercise alone for either muscle and for some myocellular parameters appeared detrimental. In summary, the periodic testing likely provided a partial exercise countermeasure for the quadriceps in the bedrest group, which is a novel finding given the extremely low exercise dose. The SPRINT exercise program appears to be viable for the quadriceps; however, refinement is needed to completely protect triceps surae myocellular and whole muscle health for astronauts on long-duration spaceflights.
This study provides unique exercise countermeasures development information for astronauts on long-duration spaceflights. The NASA SPRINT program was protective for quadriceps myocellular and whole muscle health, whereas the triceps surae (soleus) was only partially protected as has been shown with other programs. The bedrest control group data may provide beneficial information for overall exercise dose and targeting fast-twitch muscle fibers. Other unique approaches for the triceps surae are needed to supplement existing exercise programs.
In older individuals, hypertrophy from progressive resistance training (PRT) is compromised in approximately one-third of participants in exercise trials. The objective of this study was to establish ...novel relationships between baseline muscle features and/or their PRT-induced change in vastus lateralis muscle biopsies with hypertrophy outcomes. Multiple linear regression analyses adjusted for sex were performed on phenotypic data from older adults (
= 48 participants, 70.8 ± 4.5 yr) completing 14 wk of PRT. Results show that baseline muscle size associates with growth regardless of hypertrophy outcome measure fiber cross-sectional area (fCSA), β = -0.76, Adj.
< 0.01; thigh muscle area by computed tomography (CT), β = -0.75, Adj.
< 0.01; dual-energy X-ray absorptiometry (DXA) thigh lean mass, β = -0.47, Adj.
< 0.05. Furthermore, loosely packed collagen organization (CO, β = -0.44, Adj.
< 0.05) and abundance of CD11b+/CD206- immune cells (β = -0.36, Adj.
= 0.10) were negatively associated with whole muscle hypertrophy, with a significant sex interaction on the latter. In addition, a composite hypertrophy score generated using all three measures reinforces significant fiber level findings that changes in myonuclei (MN) (β = 0.67, Adj.
< 0.01), changes in immune cells (β = 0.48, Adj.
< 0.05; both CD11b+/CD206+and CD11b+/CD206- cells), and capillary density (β = 0.56, Adj.
< 0.01) are significantly associated with growth. Exploratory single-cell RNA-sequencing of CD11b+ cells in muscle in response to resistance exercise showed that macrophages have a mixed phenotype. Collagen associations with macrophages may be an important aspect in muscle response heterogeneity. Detailed histological phenotyping of muscle combined with multiple measures of growth response to resistance training in older persons identify potential new mechanisms underlying response heterogeneity and possible sex differences.
Extensive analyses of muscle features associated with muscle size and resistance training response in older persons, including sex differences, and evaluation of multiple measures of hypertrophy are discussed. Collagen organization and CD11b-expressing immune cells offer potential new targets to augment growth response in older individuals. A hypertrophy composite score reveals that changes in immune cells, myonuclei, and capillary density are critically important for overall muscle growth while sc-RNAseq reveals evidence for macrophage heterogeneity.
Resistance training (RT) remains the most effective treatment for age-related declines in muscle mass. However, many older adults experience attenuated muscle hypertrophy in response to RT when ...compared to younger adults. This may be attributed to underlying molecular processes that are dysregulated by aging and exacerbated by improperly prescribed RT weekly volume, intensity, and/or frequency doses. MicroRNA (miRNA) are key epigenetic regulators that impact signaling pathways and protein expression within cells, are dynamic and responsive to exercise stimuli, and are often dysregulated in diseases. In this study, we used untargeted miRNA-seq to examine miRNA in skeletal muscle and serum-derived exosomes of older adults (n = 18, 11M/7F, 66±1y) who underwent 3x/wk RT for 30 weeks e.g., high intensity 3x/wk (HHH, n = 9) or alternating high-low-high intensity (HLH, n = 9), after a standardized four-week wash-in. Within each tissue, miRNAs were clustered into modules based on pairwise correlation using Weighted Gene Correlation Network Analysis (WGCNA). Modules were tested for association with the magnitude of RT-induced thigh lean mass (TLM) change (as measured by DXA). While no modules were unique to training dose, we identified miRNA modules in skeletal muscle associated with TLM gains irrespective of exercise dose. Using miRNA-target interactions, we analyzed key miRNAs in significant modules for their potential regulatory involvement in biological pathways. Findings point toward potential miRNAs that may be informative biomarkers and could also be evaluated as potential therapeutic targets as an adjuvant to RT in order to maximize skeletal muscle mass accrual in older adults.
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