Key points
A hallmark trait of ageing skeletal muscle health is a reduction in size and function, which is most pronounced in the fast muscle fibres.
We studied older men (74 ± 4 years) with a ...history of lifelong (>50 years) endurance exercise to examine potential benefits for slow and fast muscle fibre size and contractile function.
Lifelong endurance exercisers had slow muscle fibres that were larger, stronger, faster and more powerful than young exercisers (25 ± 1 years) and age‐matched non‐exercisers (75 ± 2 years).
Limited benefits with lifelong endurance exercise were noted in the fast muscle fibres.
These findings suggest that additional exercise modalities (e.g. resistance exercise) or other therapeutic interventions are needed to target fast muscle fibres with age.
We investigated single muscle fibre size and contractile function among three groups of men: lifelong exercisers (LLE) (n = 21, 74 ± 4 years), old healthy non‐exercisers (OH) (n = 10, 75 ± 2 years) and young exercisers (YE) (n = 10, 25 ± 1 years). On average, LLE had exercised ∼5 days week–1 for ∼7 h week–1 over the past 53 ± 6 years. LLE were subdivided based on lifelong exercise intensity into performance (LLE‐P) (n = 14) and fitness (LLE‐F) (n = 7). Muscle biopsies (vastus lateralis) were examined for myosin heavy chain (MHC) slow (MHC I) and fast (MHC IIa) fibre size and function (strength, speed, power). LLE MHC I size (7624 ± 2765 μm2) was 25–40% larger (P < 0.001) than YE (6106 ± 1710 μm2) and OH (5476 ± 2467 μm2). LLE MHC I fibres were ∼20% stronger, ∼10% faster and ∼30% more powerful than YE and OH (P < 0.05). By contrast, LLE MHC IIa size (6466 ± 2659 μm2) was similar to OH (6237 ± 2525 μm2; P = 0.854), with both groups ∼20% smaller (P < 0.001) than YE (7860 ± 1930 μm2). MHC IIa contractile function was variable across groups, with a hierarchical pattern (OH > LLE > YE; P < 0.05) in normalized power among OH (16.7 ± 6.4 W L–1), LLE (13.9 ± 4.5 W L–1) and YE (12.4 ± 3.5 W L–1). The LLE‐P and LLE‐F had similar single fibre profiles with MHC I power driven by speed (LLE‐P) or force (LLE‐F), suggesting exercise intensity impacted slow muscle fibre mechanics. These data suggest that lifelong endurance exercise benefited slow muscle fibre size and function. Comparable fast fibre characteristics between LLE and OH, regardless of training intensity, suggest other exercise modes (e.g. resistance training) or myotherapeutics may be necessary to preserve fast muscle fibre size and performance with age.
Key points
A hallmark trait of ageing skeletal muscle health is a reduction in size and function, which is most pronounced in the fast muscle fibres.
We studied older men (74 ± 4 years) with a history of lifelong (>50 years) endurance exercise to examine potential benefits for slow and fast muscle fibre size and contractile function.
Lifelong endurance exercisers had slow muscle fibres that were larger, stronger, faster and more powerful than young exercisers (25 ± 1 years) and age‐matched non‐exercisers (75 ± 2 years).
Limited benefits with lifelong endurance exercise were noted in the fast muscle fibres.
These findings suggest that additional exercise modalities (e.g. resistance exercise) or other therapeutic interventions are needed to target fast muscle fibres with age.
Aspirin is one of the most commonly consumed cyclooxygenase (COX)‐inhibitors and anti‐inflammatory drugs and has been shown to block COX‐produced regulators of inflammation and aging skeletal muscle ...size. We used propensity score matching to compare skeletal muscle characteristics of individuals from the Health ABC study that did not consume aspirin or any other COX‐inhibiting drugs (non‐consumers, n = 497, 74 ± 3 year, 168 ± 9 cm, 75.1 ± 13.8 kg, 33.1 ± 7.4% body fat, 37% women, 34% black) to those that consumed aspirin daily (and not any other COX‐inhibiting drugs) and for at least 1 year (aspirin consumers, n = 515, 74 ± 3 year, 168 ± 9 cm, 76.2 ± 13.6 kg, 33.8 ± 7.1% body fat, 39% women, 30% black, average aspirin consumption: 6 year). Subjects were matched (p > 0.05) based on age, height, weight, % body fat, sex, and race (propensity scores: 0.33 ± 0.09 vs. 0.33 ± 0.09, p > 0.05). There was no difference between non‐consumers and aspirin consumers for computed tomography‐determined muscle size of the quadriceps (103.5 ± 0.9 vs. 104.9 ± 0.8 cm2, p > 0.05) or hamstrings (54.6 ± 0.5 vs. 54.9 ± 0.5 cm2, p > 0.05), or quadriceps muscle strength (111.1 ± 2.0 vs. 111.7 ± 2.0 Nm, p > 0.05). However, muscle attenuation (i.e., density) was higher in the aspirin consumers in the quadriceps (40.9 ± 0.3 vs. 44.4 ± 0.3 Hounsfield unit HU, p < 0.05) and hamstrings (27.7 ± 0.4 vs. 33.2 ± 0.4 HU, p < 0.05). These cross sectional data suggest that chronic aspirin consumption does not influence age‐related skeletal muscle atrophy, but does influence skeletal muscle composition in septuagenarians. Prospective longitudinal investigations remain necessary to better understand the influence of chronic COX regulation on aging skeletal muscle health.
Aspirin is one of the most commonly consumed cyclooxygenase (COX)‐inhibitors and anti‐inflammatory drugs and has been shown to block COX‐produced regulators of inflammation in human skeletal muscle. Considering the negative association between inflammation and muscle mass in older individuals, data from large scale observational studies of aging may provide insight into the role of aspirin in the control of age‐related skeletal muscle atrophy. These cross sectional data suggest that chronic aspirin consumption does not influence age‐related skeletal muscle atrophy, but does influence skeletal muscle composition in septuagenarians.
Common cyclooxygenase (COX)-inhibiting drugs enhance resistance exercise induced muscle mass and strength gains in older individuals. The purpose of this investigation was to determine whether the ...underlying mechanism regulating this effect was specific to Type I or Type II muscle fibers, which have different contractile and metabolic profiles. Muscle biopsies (vastus lateralis) were obtained before and after 12 weeks of knee-extensor resistance exercise (3 days/week) from healthy older men who consumed either a placebo (n = 8; 64±2 years) or COX inhibitor (acetaminophen, 4 gram/day; n = 7; 64±1 years) in double-blind fashion. Muscle samples were examined for Type I and II fiber cross-sectional area, capillarization, and metabolic enzyme activities (glycogen phosphorylase, citrate synthase, β-hydroxyacyl-CoA-dehydrogenase). Type I fiber size did not change with training in the placebo group (304±590 μm(2)) but increased 28% in the COX inhibitor group (1,388±760 μm(2), p < .1). Type II fiber size increased 26% in the placebo group (1,432±499 μm(2), p < .05) and 37% in the COX inhibitor group (1,825±400 μm(2), p < .05). Muscle capillarization and enzyme activity were generally maintained in the placebo group. However, capillary to fiber ratio increased 24% (p < .1) and citrate synthase activity increased 18% (p < .05) in the COX inhibitor group. COX inhibitor consumption during resistance exercise in older individuals enhances myocellular growth, and this effect is more pronounced in Type I muscle fibers.
Although aspirin is one of the most common anti-inflammatory drugs in the world, the effect of aspirin on human skeletal muscle inflammation is almost completely unknown. This study examined the ...potential effects and related time course of an orally consumed aspirin dose on the inflammatory prostaglandin E
(PGE
)/cyclooxygenase (COX) pathway in human skeletal muscle. Skeletal muscle biopsies were taken from the vastus lateralis of 10 healthy adults (5 male and 5 female, 25 ± 2 yr old) before (Pre) and 2, 4, and 24 h after (Post) a standard dose (975mg) of aspirin and partitioned for analysis of 1) in vivo PGE
levels in resting skeletal muscle and 2) ex vivo skeletal muscle PGE
production when stimulated with the COX substrate arachidonic acid (5 μM). PGE
levels in vivo and PGE
production ex vivo were generally unchanged at each time point after aspirin consumption. However, most individuals clearly showed suppression of PGE
, but at varying time points after aspirin consumption. When the maximum suppression after aspirin consumption was examined for each individual, independent of time, PGE
levels in vivo (184 ± 17 and 104 ± 23pg/g wet wt at Pre and Post, respectively) and PGE
production ex vivo (2.74 ± 0.17 and 2.09 ± 0.11pg·mg wet wt
·min
at Pre and Post, respectively) were reduced ( P < 0.05) by 44% and 24%, respectively. These results provide evidence that orally consumed aspirin can inhibit the COX pathway and reduce the inflammatory mediator PGE
in human skeletal muscle. Findings from this study highlight the need to expand our knowledge regarding the potential role for aspirin regulation of the deleterious influence of inflammation on skeletal muscle health in aging and exercising individuals. NEW & NOTEWORTHY This study demonstrated that orally consumed aspirin can target the prostaglandin/cyclooxygenase pathway in human skeletal muscle. This pathway has been shown to regulate skeletal muscle metabolism and inflammation in aging and exercising individuals. Given the prevalence of aspirin consumption, these findings may have implications for skeletal muscle health in a large segment of the population.
Twelve weeks of resistance training (3 days/wk) combined with daily consumption of the cyclooxygenase-inhibiting drugs acetaminophen (4.0 g/day; n = 11, 64 ± 1 yr) or ibuprofen (1.2 g/day; n = 13, 64 ...± 1 yr) unexpectedly promoted muscle mass and strength gains 25-50% above placebo (n = 12, 67 ± 2 yr). To investigate the mechanism of this adaptation, muscle biopsies obtained before and ∼72 h after the last training bout were analyzed for mRNA levels of prostaglandin (PG)/cyclooxygenase pathway enzymes and receptors arachidonic acid synthesis: cytosolic phospholipase A(2) (cPLA(2)) and secreted phospholipase A(2) (sPLA(2)); PGF(2α) synthesis: PGF(2α) synthase and PGE(2) to PGF(2α) reductase; PGE(2) synthesis: PGE(2) synthase-1, -2, and -3; PGF(2α) receptor and PGE(2) receptor-4, cytokines and myokines involved in skeletal muscle adaptation (TNF-α, IL-1β, IL-6, IL-8, IL-10), and regulators of muscle growth myogenin, myogenic regulatory factor-4 (MRF4), myostatin and atrophy Forkhead box O3A (FOXO3A), atrogin-1, muscle RING finger protein 1 (MuRF-1), inhibitory κB kinase β (IKKβ). Training increased (P < 0.05) cPLA(2), PGF(2α) synthase, PGE(2) to PGF(2α) reductase, PGE(2) receptor-4, TNF-α, IL-1β, IL-8, and IKKβ. However, the PGF(2α) receptor was upregulated (P < 0.05) only in the drug groups, and the placebo group upregulation (P < 0.05) of IL-6, IL-10, and MuRF-1 was eliminated in both drug groups. These results highlight prostaglandin and myokine involvement in the adaptive response to exercise in older individuals and suggest two mechanisms underlying the enhanced muscle mass gains in the drug groups: 1) The drug-induced PGF(2α) receptor upregulation helped offset the drug suppression of PGF(2α)-stimulated protein synthesis after each exercise bout and enhanced skeletal muscle sensitivity to this stimulation. 2) The drug-induced suppression of intramuscular PGE(2) production increased net muscle protein balance after each exercise bout through a reduction in PGE(2)-induced IL-6 and MuRF-1, both promoters of muscle loss.
Evidence suggests that consumption of over-the-counter cyclooxygenase (COX) inhibitors may interfere with the positive effects that resistance exercise training has on reversing sarcopenia in older ...adults. This study examined the influence of acetaminophen or ibuprofen consumption on muscle mass and strength during 12 wk of knee extensor progressive resistance exercise training in older adults. Thirty-six individuals were randomly assigned to one of three groups and consumed the COX-inhibiting drugs in double-blind placebo-controlled fashion: placebo (67 ± 2 yr; n = 12), acetaminophen (64 ± 1 yr; n = 11; 4 g/day), and ibuprofen (64 ± 1 yr; n = 13; 1.2 g/day). Compliance with the resistance training program (100%) and drug consumption (via digital video observation, 94%), and resistance training intensity were similar (P > 0.05) for all three groups. Drug consumption unexpectedly increased muscle volume (acetaminophen: 109 ± 14 cm(3), 12.5%; ibuprofen: 84 ± 10 cm(3), 10.9%) and muscle strength (acetaminophen: 19 ± 2 kg; ibuprofen: 19 ± 2 kg) to a greater extent (P < 0.05) than placebo (muscle volume: 69 ± 12 cm(3), 8.6%; muscle strength: 15 ± 2 kg), when controlling for initial muscle size and strength. Follow-up analysis of muscle biopsies taken from the vastus lateralis before and after training showed muscle protein content, muscle water content, and myosin heavy chain distribution were not influenced (P > 0.05) by drug consumption. Similarly, muscle content of the two known enzymes potentially targeted by the drugs, COX-1 and -2, was not influenced (P > 0.05) by drug consumption, although resistance training did result in a drug-independent increase in COX-1 (32 ± 8%; P < 0.05). Drug consumption did not influence the size of the nonresistance-trained hamstring muscles (P > 0.05). Over-the-counter doses of acetaminophen or ibuprofen, when consumed in combination with resistance training, do not inhibit and appear to enhance muscle hypertrophy and strength gains in older adults. The present findings coupled with previous short-term exercise studies provide convincing evidence that the COX pathway(s) are involved in the regulation of muscle protein turnover and muscle mass in humans.
Skeletal muscle atrophy is evident after muscle disuse, unloading, or spaceflight and results from decreased protein content as a consequence of decreased protein synthesis, increased protein ...breakdown or both. At this time, there are essentially no human data describing proteolysis in skeletal muscle undergoing atrophy on Earth or in space, primarily due to lack of valid and accurate methodology. This particular study aimed at assessing the effects of short-term unloading on the muscle contractile proteolysis rate. Eight men were subjected to 72-h unilateral lower limb suspension (ULLS) and intramuscular interstitial levels of the naturally occurring proteolytic tracer 3-methylhistidine (3MH) were measured by means of microdialysis before and on completion of this intervention. The 3MH concentration following 72-h ULLS (2.01 +/- 0.22 nmol/ml) was 44% higher (P < 0.05) than before ULLS (1.56 +/- 0.20 nmol/ml). The present experimental model and the employed method determining 3MH in microdialysates present a promising tool for monitoring skeletal muscle proteolysis or metabolism of specific muscles during conditions resulting in atrophy caused by, e.g., disuse and real or simulated microgravity. This study provides evidence that the atrophic processes are evoked rapidly and within 72 h of unloading and suggests that countermeasures should be employed in the early stages of space missions to offset or prevent muscle loss during the period when the rate of muscle atrophy is the highest.
To assess myosin heavy chain (MHC) plasticity in aging skeletal muscle with aerobic exercise training, MHC composition was measured at the messenger RNA (mRNA) level and protein level in mixed-muscle ...homogenates and single myofibers. Muscle samples were obtained from eight nonexercising women (70 ± 2 years) before and after 12 weeks of training (20-45 minutes of cycle exercise per session at 60%-80% heart rate reserve, three to four sessions per week). Training elevated MHC I mRNA (p < .10) and protein (p < .05) in mixed-muscle (54% ± 4% to 61% ± 2%) and single myofibers (42% ± 4% to 52% ± 3%). The increase in MHC I protein was positively correlated (p < .05) with improvements in whole muscle power. Training resulted in a general downregulation of MHC IIa and IIx at the mRNA and protein levels. The training-induced increase in MHC I protein and mRNA demonstrates the maintenance of skeletal muscle plasticity with aging. Furthermore, these data suggest that a shift toward an oxidative MHC phenotype may be beneficial for metabolic and functional health in older individuals.
Several factors affect muscle protein synthesis (MPS) in the postabsorptive state. Extreme physical inactivity (e.g., bedrest) may reduce basal MPS, whereas walking may augment basal MPS. We ...hypothesized that outpatients would have a higher postabsorptive MPS than inpatients. To test this hypothesis, we conducted a retrospective analysis. We compared 152 outpatient participants who arrived at the research site the morning of the MPS assessment with 350 Inpatient participants who had an overnight stay in the hospital unit before the MPS assessment the following morning. We used stable isotopic methods and collected vastus lateralis biopsies ∼2 to 3 h apart to assess mixed MPS. MPS was ∼12% higher (
< 0.05) for outpatients than inpatients. Within a subset of participants, we discovered that after instruction to limit activity, outpatients (
= 13) took 800 to 900 steps in the morning to arrive at the unit, seven times more steps than inpatients (
= 12). We concluded that an overnight stay in the hospital as an inpatient is characterized by reduced morning activity and causes a slight but significant reduction in MPS compared with participants studied as outpatients. Researchers should be aware of physical activity status when designing and interpreting MPS results.
The postabsorptive muscle protein synthesis rate is lower in the morning after an overnight inpatient hospital stay compared with an outpatient visit. Although only a minimal amount of steps was conducted by outpatients (∼900), this was enough to increase postabsorptive muscle protein synthesis rate.
The aim of this project was to develop a method to assess fiber type specific protein content across the continuum of human skeletal muscle fibers. Individual vastus lateralis muscle fibers (n=264) ...were clipped into two portions: one for sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS–PAGE) fiber typing and one for Western blot protein identification. Following fiber type determination, fiber segments were combined into fiber type specific pools (∼ 20fibers/pool) and measured for total protein quantity, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), citrate synthase (CS), and total p38 content. GAPDH content was 64, 54, 160, and 138% more abundant in myosin heavy chain (MHC) I/IIa, MHC IIa, MHC IIa/IIx, and MHC IIx fibers, respectively, when compared with MHC I. Inversely, CS content was 528, 472, 242, and 47% more abundant in MHC I, MHC I/IIa, MHC IIa, and MHC IIa/IIx fibers, respectively, when compared with MHC IIx. Total p38 content was 87% greater in MHC IIa versus MHC I fibers. These data and this approach establish a reliable method for human skeletal muscle fiber type specific protein analysis. Initial results show that particular proteins exist in a hierarchal fashion throughout the continuum of human skeletal muscle fiber types, further highlighting the necessity of fiber type specific analysis.
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