Senescent Skeletal Muscle Research Articles

Senescent skeletal muscle fibroadipogenic progenitors recruit and promote M2 polarization of macrophages.

Senescent cells compromise tissue structure and function in older organisms. We recently identified senescent fibroadipogenic progenitors (FAPs) with activated chemokine signaling pathways in the skeletal muscle of old mice, and hypothesized these cells may contribute to the age-associated accumulation of immune cells in skeletal muscle. In this study, through cell-cell communication analysis of skeletal muscle single-cell RNA-sequencing data, we identified unique interactions between senescent FAPs and macrophages, including those mediated by Ccl2 and Spp1. Using mouse primary FAPs invitro, we verified increased expression of Ccl2 and Spp1 and secretion of their respective proteins in the context of both irradiation- and etoposide-induced senescence. Compared to non-senescent FAPs, the medium of senescent FAPs markedly increased the recruitment of macrophages in an invitro migration assay, an effect that was mitigated by preincubation with antibodies to either CCL2 or osteopontin (encoded by Spp1). Further studies demonstrated that the secretome of senescent FAPs promotes polarization of macrophages toward an M2 subtype. These data suggest the unique secretome of senescent FAPs may compromise skeletal muscle homeostasis by recruiting and directing the behavior of macrophages.

Ginsenoside Rb1 Prevents Oxidative Stress-Induced Apoptosis and Mitochondrial Dysfunction in Muscle Stem Cells via NF-κB Pathway.

Sarcopenia, featured by the progressive loss of skeletal muscle function and mass, is associated with the impaired function of muscle stem cells (MuSCs) caused by increasing oxidative stress in senescent skeletal muscle tissue during aging. Intact function of MuSCs maintains the regenerative potential as well as the homeostasis of skeletal muscle tissues during aging. Ginsenoside Rb1, a natural compound from ginseng, exhibited the effects of antioxidation and against apoptosis. However, its effects of restoring MuSC function during aging and improving age-related sarcopenia remained unknown. In this study, we investigated the role of Rb1 in improving MuSC function and inhibiting apoptosis by reducing oxidative stress levels. We found that Rb1 inhibited the accumulation of reactive oxygen species (ROS) and protected the cells from oxidative stress to attenuate the H2O2-induced cytotoxicity. Rb1 also blocked oxidative stress-induced apoptosis by inhibiting the activation of caspase-3/9, which antagonized the decrease in mitochondrial content and the increase in mitochondrial abnormalities caused by oxidative stress via promoting the protein expression of genes involved in mitochondrial biogenesis. Mechanistically, it was proven that Rb1 exerted its antioxidant effects and avoided the apoptosis of myoblasts by targeting the core regulator of the nuclear factor-kappa B (NF-κB) signal pathway. Therefore, these findings suggest that Rb1 may have a beneficial role in the prevention and treatment of MuSC exhaustion-related diseases like sarcopenia.

Lifelong Aerobic Exercise Alleviates Sarcopenia by Activating Autophagy and Inhibiting Protein Degradation via the AMPK/PGC-1α Signaling Pathway.

Sarcopenia is an aging-induced syndrome characterized by a progressive reduction of skeletal muscle mass and strength. Increasing evidence has attested that appropriate and scientific exercise could induce autophagy or optimize the functional status of autophagy, which plays a critical role in senescent muscular dystrophy. As a publicly recognized strategy for extending lifespan and improving the health of the elderly, the underlying mechanisms of lifelong regular aerobic exercise for the prevention of sarcopenia have not been fully elucidated. To explore the role of lifelong aerobic exercise in the beneficial regulation of autophagic signaling pathways in senescent skeletal muscle, the natural aging mice were used as the sarcopenia model and subjected to lifelong treadmill running to evaluate corresponding parameters related to skeletal muscle atrophy and autophagic signaling pathways. Compared with the young control mice, the aged mice showed a significant reduction in skeletal muscle mass, gastrocnemius muscle weight/body weight (GMW/BW) ratio, and cross-sectional areas (CSA) of skeletal muscle fibers (p < 0.01). In contrast, lifelong aerobic exercise effectively rescued these reduced biomarkers associated with muscle atrophy. Moreover, as shown in the activated AMPK/PGC-1α signaling pathway, lifelong aerobic exercise successfully prevented the aging-induced impairment of the ubiquitin-proteasome system (UPS), excessive apoptosis, defective autophagy, and mitochondrial dysfunction. The exercise-induced autophagy suppressed the key regulatory components of the UPS, inhibited excessive apoptosis, and optimized mitochondrial quality control, thereby preventing and delaying aging-induced skeletal muscle atrophy.

Bone and Muscle Crosstalk in Aging.

Osteoporosis and sarcopenia are two age-related diseases that affect the quality of life in the elderly. Initially, they were thought to be two independent diseases; however, recently, increasing basic and clinical data suggest that skeletal muscle and bone are both spatially and metabolically connected. The term “osteosarcopenia” is used to define a condition of synergy of low bone mineral density with muscle atrophy and hypofunction. Bone and muscle cells secrete several factors, such as cytokines, myokines, and osteokines, into the circulation to influence the biological and pathological activities in local and distant organs and cells. Recent studies reveal that extracellular vesicles containing microRNAs derived from senescent skeletal muscle and bone cells can also be transported and aid in regulating bone-muscle crosstalk. In this review, we summarize the age-related changes in the secretome and extracellular vesicle-microRNAs secreted by the muscle and bone, and discuss their interactions between muscle and bone cells during aging.

The Mechanism of Decline of Senescent Skeletal Muscle Satellite Cell Self-Renewal and Regenerative Proliferation: The Role of Heparan Sulfate-FGF-2--FGFR1-p38αMAPK Axis, Sprouty1, miR-1, miR-133 and miR-29a

Aging mammalian skeletal muscle satellite cells (MuSCs) undergo a decline of stem cell/progenitor cell proliferative and regenerative capacity, and the development of a physiological milieu characteristic of a state of chronic sterile inflammation. p38αMAPK and ERK1/2 are two major signaling pathways that regulate the age-associated decline of MuSC proliferative capacity. In this review we propose the following mechanism that links the p38αMAPK pathway to the decline of self-renewal and regenerative capacity of aged MuSCs: a) the HS-FGF-2-FGFR1-p38αMAPK-Axis, a tightly linked homeostatic signaling complex, is in synchrony with the autoinhibition of FGFR1; b) autoinhibition contributes to the Axis’ regulation of the homeostasis of P-p38αMAPK activity in juvenile MuSC; c) this combination of protein-protein interactions is characteristic of a juvenile cytoplasmic milieu of beneficial P-p38αMAPK activity and d) includes Sprouty1 inhibition that supports the stimulation of FGF-2 --&gt; miR-29a; e) the miR29a dismantles the basement membrane in preparation for the initiation of replication; f) an age-associated impaired, dysregulated, over-sulfated heparan sulfate ligand (HS)-FGF-2 fails to activate FGFR1 in aged MuSCs; g) this uncouples its regulation of p38αMAPK and ERK1/2 pathways and results in desensitization of FGFR1; h) desensitization of FGFR1 and Sprouty1 interaction in aged MuSC uncouples their regulation of P-p38αMAPK in the aged MuSCs; i) this enables a state of chronic sterile inflammation to promote and sustain an increased level of P-p38αMAPK activity; and, j) the increased activity of P-p38αMAPK in aged MuSC stimulates the production of cell cycle inhibitors, miR-1 and miR-133, thereby attenuating the expression of the cell cycle regulators, SP1 and cyclin D1, resulting in a G1/S arrest; j) the increased level of p38αMAPK activity promotes the apoptosis of the aged activated MuSCs. This mechanism involves the synergistic interactions of HS-FGF2-FGFR-1, Sprouty (spry1), miR-1, miR-133 and miR-29a that unify the extracellular niche and intracellular milieu for the juvenile vs age-associated regulation of proliferative capacity of the MuSC. Our hypothesis unifies these interactions with the role of the extracellular niche and intracellular milieu in the stimulation of juvenile proliferation vs age-associated decline of skeletal muscle satellite cell self-renewal and regenerative proliferation. Word Count = 344

Senescent Skeletal Muscle Produces a Distinct Cytokine Secretory Profile in Response to Endotoxin Exposure in Vitro

Skeletal muscles are thought to contribute to both pathogen detection and cytokine secretion as a part of the innate immune response. Skeletal muscle fibers contain toll like receptors (TLRs) that bind a wide array of bacterial, viral, and fungal ligands, inducing signal transduction and subsequent cytokine production. Aging populations have significantly greater mortality annually from influenza, incidence of bacterial and fungal infections, and diminished vaccine efficacy. In senescent mice, macrophage TLR expression and cytokine secretion are known to decline in some tissues. It is unknown if skeletal muscle also exhibits age associated changes in innate immune contribution. The objective of this experiment was to determine if there are alterations in cytokine secretory response of aged skeletal muscle to lipopolysaccharide (LPS), a potent TLR2 and TLR4 ligand.Matched solei muscles from 12–15‐week‐old male C57BL/6 mice (n=8; “young”) and 16‐month‐old (n=10; “old”) were excised in oxygenated (95%O2/5%CO2) Krebs solution and placed under 1 g of tension in 2 ml baths at 35°C. After a 30‐min acclimation period (T0), the buffer was changed and muscles were exposed to 1 μg/ml LPS. Bath samples at T0, 1 hr (T1) and 2 hr (T2) were taken, combined with a protease inhibitor cocktail and frozen at −80°C prior to Luminex multiplex analysis.In conclusion, solei from old mice generally displayed a diminished cytokine secretory response, with particularly large decrements in IL‐12p70, IL‐6, MCP‐1, KC, and G‐CSF compared to young controls (see Table 1). Interestingly, solei from old mice displayed relatively large increases in IL‐1α, with smaller, yet also significant increases in IL‐10 and TNFα. The drastically lowered IL‐6 secretion in older mice may diminish the normal inhibition on IL‐1α and subsequent TNFα production. The small rise in IL‐10 in the elder mice may serve as a compensatory mechanism to lower IL‐1α due to diminished IL‐6 response. It may also contribute towards the severely lowered KC production, as is seen with the inhibition of human KC homologue IL‐8 by elevated IL‐10. The combination of radically lower IL‐6 and KC secretion, and increased IL‐1α and TNFα may produce an environment favoring excessive inflammatory, yet reduced chemotactic responses to pathogen exposure in older mice.Support or Funding InformationSupported by NIGMS R01GM118895‐01 and the BK and Betty Stevens Endowment.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Spermidine coupled with exercise rescues skeletal muscle atrophy from D-gal-induced aging rats through enhanced autophagy and reduced apoptosis via AMPK-FOXO3a signal pathway.

The quality control of skeletal muscle is a continuous requirement throughout the lifetime, although its functions and quality present as a declining trend during aging process. Dysfunctional or deficient autophagy and excessive apoptosis may contribute to the atrophy of senescent skeletal muscle. Spermidine, as a natural polyamine, can be involved in important cellular functions for lifespan extension and stress resistance in several model organisms through activating autophagy. Similarly, cellular autophagic responses to exercise have also been extensively investigated. In the present study, in order to confirm the mitigation or amelioration of skeletal muscle atrophy in aging rats through spermidine coupled with exercise intervention and explore corresponding mechanisms, the rat model with aging-related atrophy of skeletal muscle was established by intraperitoneal injection of D-galactose (D-gal) (200 mg/kgd), and model rats were subjected to the intervention with spermidine (5 mg/kgd) or swimming (60 min/d, 5 d/wk) or combination for 42 days. Spermidine coupled with exercise could attenuate D-gal-induced aging-related atrophy of skeletal muscle through induced autophagy and reduced apoptosis with characteristics of more autophagosomes, activated mitophagy, enhanced mitochondrial quality, alleviated cell shrinkage, and less swollen mitochondria under transmission scanning microscopic observation. Meanwhile, spermidine coupled with exercise could induce autophagy through activating AMPK-FOXO3a signal pathway with characterization of increased Beclin1 and LC3-II/LC3-I ratio, up-regulated anti-apoptotic Bcl-2, down-regulated pro-apoptotic Bax and caspase-3, as well as activated AMPK and FOXO3a. Therefore, spermidine combined with exercise can execute the prevention or treatment of D-gal-induced aging-related skeletal muscle atrophy through enhanced autophagy and reduced apoptosis mediated by AMPK-FOXO3a signal pathway.

Acute Treatment of Resveratrol Alleviates Doxorubicin-Induced Myotoxicity in Aged Skeletal Muscle Through SIRT1-Dependent Mechanisms.

Study of the exacerbating effects of chemotherapeutics, such as doxorubicin, on the impairment of insulin metabolic signaling in aged skeletal muscle is very limited. Here, we tested the hypothesis that activation of sirtuin 1 deacetylase activity by resveratrol would prevent the disruption of insulin signaling and augmentation of catabolic markers induced by doxorubicin in aged skeletal muscle. Two- and 10-month-old senescence-accelerated mice (prone 8) were randomized to receive saline, doxorubicin, doxorubicin and resveratrol, or a combination of doxorubicin, resveratrol, and sirtinol or EX527. Doxorubicin reduced the sirtuin 1 activity without affecting the phosphorylation levels of IRS1(Ser307), mTOR(Ser2481), Akt(Thr308/Ser473), membranous glucose transporter 4, protein abundance of PDK4, and enzymatic activity of pyruvate dehydrogenase in aged muscles. Intriguingly, resveratrol attenuated the doxorubicin-induced elevations of apoptotic and catabolic markers measured as Bax, caspase 3 activity, apoptotic DNA fragmentation, MuRF-1, ubiquitinated proteins, and proteasomal activity in aged muscles, whereas these beneficial effects were abolished on inhibition of sirtuin 1 by sirtinol or EX527. Markers of insulin signaling were not affected by doxorubicin or resveratrol in the senescent skeletal muscle. Nevertheless, the antiapoptotic and anticatabolic effects of resveratrol in aged skeletal muscle treated with doxorubicin were mediated in a sirtuin 1-dependent signaling manner.

Denervation Causes Fiber Atrophy and Myosin Heavy Chain Co-Expression in Senescent Skeletal Muscle

Although denervation has long been implicated in aging muscle, the degree to which it is causes the fiber atrophy seen in aging muscle is unknown. To address this question, we quantified motoneuron soma counts in the lumbar spinal cord using choline acetyl transferase immunhistochemistry and quantified the size of denervated versus innervated muscle fibers in the gastrocnemius muscle using the in situ expression of the denervation-specific sodium channel, Nav1.5, in young adult (YA) and senescent (SEN) rats. To gain insights into the mechanisms driving myofiber atrophy, we also examined the myofiber expression of the two primary ubiquitin ligases necessary for muscle atrophy (MAFbx, MuRF1). MN soma number in lumbar spinal cord declined 27% between YA (638±34 MNs×mm−1) and SEN (469±13 MNs×mm−1). Nav1.5 positive fibers (1548±70 μm2) were 35% smaller than Nav1.5 negative fibers (2367±78 μm2; P<0.05) in SEN muscle, whereas Nav1.5 negative fibers in SEN were only 7% smaller than fibers in YA (2553±33 μm2; P<0.05) where no Nav1.5 labeling was seen, suggesting denervation is the primary cause of aging myofiber atrophy. Nav1.5 positive fibers had higher levels of MAFbx and MuRF1 (P<0.05), consistent with involvement of the proteasome proteolytic pathway in the atrophy of denervated muscle fibers in aging muscle. In summary, our study provides the first quantitative assessment of the contribution of denervation to myofiber atrophy in aging muscle, suggesting it explains the majority of the atrophy we observed. This striking result suggests a renewed focus should be placed on denervation in seeking understanding of the causes of and treatments for aging muscle atrophy.

POINT: IGF IS THE MAJOR PHYSIOLOGICAL REGULATOR OF MUSCLE MASS

The insulin-like growth factors (IGFs)-I and -II are homologous peptides that are structurally related to insulin. However, IGFs retain the C-peptide, enabling binding to their main signaling receptor, the IGF type 1 receptor (IGF1R). IGF-II, however, can also bind to and signal via the A isoform of

Drastic increase of myosin light chain MLC-2 in senescent skeletal muscle indicates fast-to-slow fibre transition in sarcopenia of old age

The age-dependent decline in skeletal muscle mass and function is believed to be due to a multi-factorial pathology and represents a major factor that blocks healthy aging by increasing physical disability, frailty and loss of independence in the elderly. This study has focused on the comparative proteomic analysis of contractile elements and revealed that the most striking age-related changes seem to occur in the protein family representing myosin light chains (MLCs). Comparative screening of total muscle extracts suggests a fast-to-slow transition in the aged MLC population. The mass spectrometric analysis of the myofibril-enriched fraction identified the MLC2 isoform of the slow-type MLC as the contractile protein with the most drastically changed expression during aging. Immunoblotting confirmed an increased abundance of slow MLC2, concomitant with a switch in fast versus slow myosin heavy chains. Staining of two-dimensional gels of crude extracts with the phospho-specific fluorescent dye ProQ-Diamond identified the increased MLC2 spot as a muscle protein with a drastically enhanced phosphorylation level in aged fibres. Comparative immunofluorescence microscopy, using antibodies to fast and slow myosin isoforms, confirmed a fast-to-slow transformation process during muscle aging. Interestingly, the dramatic increase in slow MLC2 expression was restricted to individual senescent fibres. These findings agree with the idea that aged skeletal muscles undergo a shift to more aerobic-oxidative metabolism in a slower-twitching fibre population and suggest the slow MLC2 isoform as a potential biomarker for fibre type shifting in sarcopenia of old age.

Diminished contraction‐induced intracellular signaling in aged fast‐twitch skeletal muscle with low and high mitochondrial content

Reduced plasticity of senescent skeletal muscle may be due to an attenuated signaling response to contractions. The intent of the present study was to determine whether aging affects signaling pathways involved in mitochondrial biogenesis in response to a single bout of contractile activity (CA). Acute stimulation (1 Hz, 5 min) of the tibialis anterior (TA) resulted in a significantly greater rate of fatigue in 36 month (mo) relative to 6 mo F344XBN rats. To investigate fiber type-specific signaling, the TA was sectioned into red (RTA) and white (WTA) portions, possessing 2.5-fold differences in mitochondrial content. The CA-mediated activation of p38, MKK3/6, CaMKII and AMPK signaling was assessed. In general, CA-evoked kinase phosphorylation was greater in RTA compared to WTA in both age groups. p38 activation was similar in RTA from 6 and 36 mo groups, however in WTA, the response was 2-fold greater in muscle from 6, relative to 36 mo animals. CA also increased MKK3/6 phosphorylation, the upstream regulator of p38, however the magnitude was 70–80% higher in RTA and WTA of 6, compared to 36 mo rats. Contraction-induced CaMKII phosphorylation was 40% higher in both fiber types in muscle from 6 relative to 36 mo animals. AMPK was not responsive to 1 Hz CA at either age. Thus, CA-induced signaling to mitochondrial biogenesis is reduced in aging muscle, but the extent of the attenuation depends in part on mitochondrial content.

Sarcopenia is not due to lack of regenerative drive in senescent skeletal muscle

Sarcopenia, loss of skeletal muscle mass, is a hallmark of aging commonly attributed to a decreased capacity to maintain muscle tissue in senescence, yet the mechanism behind the muscle wasting remains unresolved. To address these issues we have explored a rodent model of sarcopenia and age-related sensorimotor impairment, allowing us to discriminate between successfully and unsuccessfully aged cohort members. Immunohistochemistry and staining of cell nuclei revealed that senescent muscle has an increased density of cell nuclei, occurrence of aberrant fibers and fibers expressing embryonic myosin. Using real-time PCR we extend the findings of increased myogenic regulatory factor mRNA to show that very high levels are found in unsuccessfully aged cohort members. This pattern is also reflected in the number of embryonic myosin-positive fibers, which increase with the degree of sarcopenia. In addition, we confirm that there is no local down-regulation of IGF-I and IGF-IR mRNA in aged muscle tissue; on the contrary, the most sarcopenic individuals showed significantly higher local expression of IGF-I mRNA. Combined, our results show that the initial drive to regenerate myofibers is most marked in cases with the most advanced loss of muscle mass, a pattern that may have its origin in differences in the rate of tissue deterioration and/or that regenerating myofibers in these cases fail to mature into functional fibers. Importantly, the genetic background is a determinant of the pace of progression of sarcopenia.

Heart transplantation changes the expression of distinct gene families.

We took advantage of the combination of a rat heart transplantation model with a modified differential display RT-PCR method to identify transcriptome changes in the right atria from transplanted compared with native hearts. Based on sequence homology search, the 37 cDNAs differentially displayed both 2 and 7 days posttransplantation were categorized into 7 unknown transcripts, 16 expressed sequence tags (ESTs), and 14 partially or completely characterized genes. The last group cDNAs, validated by relative RT-PCR, belonged to diverse gene families involved in specific metabolisms, protein synthesis, cell signaling, and transcription. Furthermore, we identified differential transcripts corresponding to denervation and fetal gene reexpression. We found coordinate downregulation of genes involved in energy metabolism and protein synthesis regulation, similar to that reported for senescent skeletal muscle. From these transcriptome changes, we propose that heart transplants and senescent muscles share common molecular mechanisms.

Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle.

Aging skeletal muscles suffer a steady decline in mass and functional performance, and compromised muscle integrity as fibrotic invasions replace contractile tissue, accompanied by a characteristic loss in the fastest, most powerful muscle fibers. The same programmed deficits in muscle structure and function are found in numerous neurodegenerative syndromes and disease-related cachexia. We have generated a model of persistent, functional myocyte hypertrophy using a tissue-restricted transgene encoding a locally acting isoform of insulin-like growth factor-1 that is expressed in skeletal muscle (mIgf-1). Transgenic embryos developed normally, and postnatal increases in muscle mass and strength were not accompanied by the additional pathological changes seen in other Igf-1 transgenic models. Expression of GATA-2, a transcription factor normally undetected in skeletal muscle, marked hypertrophic myocytes that escaped age-related muscle atrophy and retained the proliferative response to muscle injury characteristic of younger animals. The preservation of muscle architecture and age-independent regenerative capacity through localized mIgf-1 transgene expression suggests clinical strategies for the treatment of age or disease-related muscle frailty.

The nucleotide-binding site of the sarcoplasmic reticulum Ca-ATPase is conformationally altered in aged skeletal muscle.

Cellular conditions in senescent skeletal muscle have been shown to result in the loss of conformational stability of the sarcoplasmic reticulum (SR) Ca-ATPase. To identify underlying structural features of age-modified Ca-ATPase, we have utilized the fluorescence properties of protein-bound probes to assess both local and global structure. We find conformational changes that include an age-related decrease in the apparent binding affinity to high affinity calcium sites detected by fluorescence signals in both tryptophans within nearby membrane-spanning helices and fluorescein isothiocyanate (FITC) bound distally to Lys(515) within the nucleotide-binding site. In addition, a substantial (80%) age-related increase in the accessibility to soluble quenchers of fluorescence of FITC is observed without concomitant changes in bimolecular quenching constants (k(q)) for protein-bound IAEDANS, also within the nucleotide-binding domain, and tryptophans within the membrane. Using fluorescence resonance energy transfer to measure distances between IAEDANS and FITC across the nucleotide-binding domain, we find no significant age-related change in the mean donor-acceptor distance; however, significant increases are observed in the conformational heterogeneity of this domain, as assessed by the width at half-maximum (HW) of the distance distribution, increasing with age from 29.4 +/- 0.8 A to 42.5 +/- 1. 1 A. Circular dichroism indicates that the average secondary structure is unaltered with age. Thus, these data suggest tertiary structural alterations in specific regions around the nucleotide-binding site rather than global conformational changes.

Changes in Skeletal Muscle with Aging

There is an approximate 30% decline in muscle strength and a 40% reduction in muscle area between the second and seventh decades of life. Thus, the loss of muscle mass with aging appears to be the major factor in the age-related loss of muscle strength. The loss of muscle mass is partially due to a significant decline in the numbers of both Type I and Type II muscle fibers plus a decrease in the size of the muscle cells, with the Type II fibers showing a preferential atrophy. There appears to be no loss of glycolytic capacity in senescent skeletal muscle whereas muscle oxidative enzyme activity and muscle capillarization decrease by about 25%. Vigorous endurance exercise training in older people, where the stimulus is progressively increased, elicits a proliferation of muscle capillaries, an increase in oxidative enzyme activity, and a significant improvement in VO2max. Likewise, progressive resistive training in older individuals results in muscle hypertrophy and increased strength, if the training stimulus is of a sufficient intensity and duration. Since older individuals adapt to resistive and endurance exercise training in a similar fashion to young people, the decline in the muscle's metabolic and force-producing capacity can no longer be considered as an inevitable consequence of the aging process. Rather, the adaptations in aging skeletal muscle to exercise training may prevent sarcopenia, enhance the ease of carrying out the activities of daily living, and exert a beneficial effect on such age-associated diseases as Type II diabetes, coronary artery disease, hypertension, osteoporosis, and obesity.

Effect of Exercise Training on Antioxidant and Metabolic Functions in Senescent Rat Skeletal Muscle

Aging is known to be associated with alterations of both oxidative capacity and antioxidant status in skeletal muscle. In the present investigation we compared the activity of enzymes involved in both metabolic functions and antioxidant defense capacity in young adult (5 months old) and senescent (27.5 months old) Fischer 344 rats. In addition, we studied the effects of chronic exercise training on these enzymes in the senescent skeletal muscle. Old sedentary rats had significantly lower glutathione peroxidase (GPX) activity (-22%, p less than 0.05) in the deep portion of vastus lateralis muscle (DVL) than young sedentary rats, but after a progressive 10-week treadmill training program GPX activity in DVL was significantly increased in old rats to a level higher than that seen in young sedentary rats. Superoxide dismutase and catalase activities in the DVL were not altered significantly with aging or by training. Glutathione S-transferase activity in the same muscle was elevated (p less than 0.05) with aging but unaffected by training. Citrate synthase and malate dehydrogenase activities in the DVL muscle were significantly decreased in senescence, whereas training increased these two enzyme activities by 71 and 48%, respectively (both p less than 0.05). Lactate dehydrogenase activity in the same muscle decreased with age but increased 23% (p less than 0.05) in old rats. These data indicate that while aging may significantly affect antioxidant and metabolic capacities in skeletal muscle, regular exercise can preserve functions of these enzyme systems at old age.