Medicine & Science in Sports & Exercise:
BASIC SCIENCES: Original Investigations
Aging does not attenuate plantaris muscle hypertrophy in male Fischer 344 rats
LINDERMAN, JON K.; BLOUGH, ERIC R.
The Laboratory of Basic and Applied Myology, Department of Physical Activity and Educational Services, The Ohio State University, Columbus, OH
Submitted for publication February 2000.
Accepted for publication March 2002.
LINDERMAN, J. K., and E. R. BLOUGH. Aging does not attenuate plantaris muscle hypertrophy in male Fischer 344 rats. Med. Sci. Sports Exerc., Vol. 34, No. 7, pp. 1115–1119, 2002.
Purpose: The present study examined the effect of extreme old age on the plasticity of the rat plantaris muscle in response to an increase in mechanical load.
Methods: Male Fischer 344 rats, aged 7 months (adult) and 25 months (old) underwent bilateral surgical ablation of the gastrocnemius muscle to functionally overload (OV) the fast-twitch plantaris muscle for 8 wk
Results: At 27 months of age, plantaris wet weight and cross-sectional area (CSA) were unaffected by age, but aging decreased peak isometric tension (Po) 27% (P < 0.05). Plantaris muscle myosin heavy chain composition indicated a loss of faster myosin heavy chains (MHC) isoforms with concomitant increases in slower MHC in old rats (P < 0.05). In adult rats, OV increased muscle CSA and Po 72% and 83%, respectively (P < 0.05). Similarly, OV increased CSA and Po 69% and 73%, respectively, in old rats (P < 0.05). Average fiber CSA increased 57% and 68% in adult-OV and old-OV rats, respectively (P < 0.05).
Conclusion: Collectively, our data indicate that plantaris muscle mass and plasticity in response to increased mechanical load are well conserved in very aged male Fischer 344 rats.
Muscle mass is a primary determinant of muscular strength. Cross-sectional studies of elderly humans (10,11,17,19,24,31,32) and rodents (1–4,9,12,15,21,28) report decreased muscle strength and muscle mass. In addition, skeletal muscle from aged mammals is characterized by a decrease in fast Type II muscle fiber size and number, and a decrease in faster myosin heavy chain isoforms (1,3,4,15,17). This decrease in Type II characteristics may negatively affect the ability to generate muscular power necessary for mobility and activities of daily living. In aged rats, loss in muscle force and Type II characteristics are commonly observed, with little or no change in muscle mass (7,15). This later observation suggests that loss in muscle strength and fast muscle characteristics may precede loss of muscle mass.
Hypertrophy of muscle cells in response to an increase in mechanical load is associated with an increase in muscle force in mammalian species (1,16,18,22,27). Cross-sectional studies in humans indicate that resistance training attenuates age-associated declines in muscle strength (13,17,30–32) and alters the coexpression of myosin isoforms (13,30). However, previous research in the very aged, those beyond the seventh decade of life, has indicated that the capacity for skeletal muscle to increase in mass in response to resistance training may (10) or may not be evident (11). Due to the many limitations associated with longitudinal gerentological studies in humans, numerous studies examining the effects of aging on skeletal muscle, particularly alterations in muscle morphology and function, have utilized aging rats (1–5,15,28,29).
Previous studies have indicated that the capacity for muscle hypertrophy in response to functional overload (7,21,28) is conserved in aging rodent muscle, but relatively little is known as to whether the increased mass improved muscle force. Further, these studies were conducted on relatively young outbred rats (25 months) housed either in unspecified conditions (7) or nonbarrier conditions (21,28). Age, relative to life expectancy, rodent strain, and housing conditions are important sources of variation in longitudinal gerentological studies using rodents (6,20,25).
We have recently reported no increase in muscle mass, fiber cross-sectional area (CSA), or muscle function in response to 8 wk of functional overload in the plantaris muscle from 38 month-old male Fischer 344 x Brown-Norway hybrid rats (1), raised and maintained in barrier conditions. Probability of survival curves generated by the National Institute of Aging (NIA) indicate that 36- to 38-month-old Fischer 344 x Brown-Norway rats correspond roughly to humans in their seventh to eight decade of life when muscle atrophy and dysfunction are prominent (17,19). However, like outbred rodent strains, the use of hybrid rats may increase variability within and between experiments; thus, the use of inbred Fischer 344 rats from the NIA greatly reduces genetic variability.
The purpose of this study was to determine whether the plantaris muscle of adult (7 month) and very aged male Fischer 344 rats (25 months) undergo similar alterations in muscle mass, fiber CSA, and physiology after 8 wk of functional overload (OV). Fischer 344 rats at 25–27 months of age correspond to humans in their seventh to eight decade of life, similar to Fischer 344 x Brown-Norway rats used previously (1). Further, the present study examines the relationship between muscle mass and muscle strength as a function of age, increased mechanical load, and the interaction between these two variables.
Animal care and use.
All procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animals as approved by the Council of the American Physiological Society and the Institutional Laboratory Animal Care and Use Committee of The Ohio State University (#95A0191). Twelve adult (7 months) and aged male Fischer 344 (old; 25 month) rats were obtained from the National Institute on Aging (NIA) and randomly assigned to either control (N = 6 per age group) or overload (OV;N = 6 per age group) treatments. Because muscle atrophy and dysfunction in humans accelerates during the eighth decade of life, probability of survival curves generated by the NIA were employed to ensure that old rats used corresponded roughly to humans in their seventh to eighth decade of life. The probability of survival for old rats was approximately 20%.
Rats were barrier housed individually in an AAALAC (Association for Assessment and Accreditation of Laboratory Animal Care) approved vivarium. Housing conditions consisted of a 12-h:12-h dark-light cycle, and temperature was maintained at 22 ± 2° C. Animals were provided food and water ad libitum and allowed to recover from shipment for at least 2 wk before experimentation began. During this time, rats were weighed weekly and carefully observed for signs of failure to thrive, such as precipitous weight loss, disinterest in the environment, or unexpected gait alterations.
As described previously (1,18), rats were anesthetized with a ketamine-xylazine cocktail (50 mg·kg−1 i.p.) and supplemented as necessary for reflexive response. In an aseptic environment the dorsal surface of the hind limb was shaved, cleaned, and the superficial musculature exposed by means of a proximal to distal incision through the skin and blunt separation of the skin and fasciae. The medial gastrocnemius and the proximal two thirds of the lateral head of the gastrocnemius were carefully isolated by blunt manipulation of the tissues and removed bilaterally. Care was taken to leave the nerve and vasculature supply to the remaining musculature undisturbed. Incomplete removal of the synergists was done to ensure that the nerve and vascular supply remained intact. After recovery from anesthesia, animals were returned to their cages and maintained in barrier housing for 8 wk.
The plantaris muscle was chosen for study because previous investigations suggest that muscle atrophy during aging is greatest in Type II fibers (15). The plantaris, composed predominantly of Type II fibers, offers a better opportunity to observe the maximal anatomic and physiologic effects on fast-twitch fibers. In addition, the plantaris muscle of young animals undergoes a large amount of hypertrophy in response to functional overload imposed by the surgical ablation of synergists (1,16,18,23,27).
Measurement of contractile properties.
As described previously (1), measurements of isometric muscle function were made in vitro at 24°C in oxygenated (95% O2, 5% CO2) Krebs-Ringer bicarbonate (pH 7.4) supplemented with 25 μM tubocurarine chloride (1,16,23). The distal tendon of the plantaris muscle was sutured (2.0 silk) to a piezoelectric force transducer (Model 200B, Piezoelectronics, New York, NY) with the proximal end (origin) attached to a rigid post. Optimal muscle length (Lo), defined as the length at which twitch tension (Pt) was peak (1), was determined within 2 min of immersion of the muscle in the chamber. After determination of Lo, maximal tetanic tension (Po) was measured with 0.2-ms duration, supramaximal voltage, and stimulation frequencies of 100 and 150 Hz (S48 Stimulator, Grass Industries, Cambridge, MA). The stimulus train duration was 500 ms, and the time between stimulation trains was 2 min. Data acquisition was accomplished by interfacing the force transducer with a Nicolet two channel digital oscilloscope (Model 720B, Oxford, U.K.) along with a CompuAdd 386 personal computer.
After measurement of contractile properties, muscles were blotted dry, trimmed of visible fat and tendon projections, and immediately weighed. Muscles were then fixed at in situ length and coated with imbedding compound (OCT, Fisher Pharmaceutical, Cincinnati, OH) and immediately frozen in isopentane cooled by liquid nitrogen. Muscles were stored below −80°C pending subsequent analysis. Whole muscle CSA was estimated as previously reported, using algorithms previously published (1,16). Sectioning for all histological staining was performed in a cryostat (American Optical, Buffalo, NY) chilled to −20°C. Sections of the mid-belly of the plantaris were cut at a thickness of 10 μm, collected on glass slides and stored in airtight containers at −20°C until use. After a preincubation at pH 4.55, fiber types were determined using standard myosin ATPase incubations at pH 9.4, as described elsewhere (1,14,30). ATPase-incubated sections were used for the determination of fiber areas, as described previously (1,14). The area of at least 100 intact fiber of each type, if present, was measured for the determination of fiber areas.
Muscle fiber cross-sections were projected at an objective magnification of 25× to a computer (CompuAdd 316s) equipped with software to measure fiber CSA (Java Jandel Video Analysis Software, Corte Madera CA). The captured image of a fiber was traced on a video monitor by using a hand-held mouse. The software package was calibrated to determine the area in μm2. Fiber cross-sectional area was determined for Type I, IIA, and IIX/IIB fiber types (Fig. 1). Average fiber CSA was determined for each muscle from the mean of all fibers traced for that muscle. To reduce experimental bias in the selection of fibers for measurement, all of the fibers on randomly selected screens were quantified. All area measurements were performed with the researcher blinded to the treatment of each respective section. Tracing of fibers was practiced until a coefficient of variance of less than 5% was repeatedly achieved. A 15- to 20-mg section of the midbelly of the muscle was used for analysis of myosin heavy chains (MHC) by using sodium dodecyl sulfate polyacrylamide gel electrophoresis as described previously (1,18,26) (Fig. 2). Due to the well know effects of overload (OV) on MHC composition, only the effect of aging on MHC composition was assessed presently.
Data are presented as means ± SE. A two-way analysis of variance (ANOVA) was used to assess the effects of age and mechanical load on all physiological and histochemical variables. The effect of aging on MHC composition was assessed with a one-way ANOVA and, where appropriate, a Scheffe post hoc test. The level of significance accepted a priori was P < 0.05.
Indices of aging.
Body mass was significantly greater in old rats, but plantaris mass, as determined by wet weight and whole muscle CSA, was unaffected by aging (Table 1). Neither average fiber CSA nor the CSA of Type I, IIA, or IIX/IIB was altered with aging (Fig. 3). The MHC composition of the plantaris muscle indicated a loss of faster MHC isoforms with concomitant increases in slower MHC with aging (Fig. 4). Aging increased Type I and IIX MHC from 3.5 ± 0.3 and 49.9 ± 1.1% in adult rats, respectively, to 5.2 ± 0.2 and 55.8 ± 1.2% in old animals, respectively (P < 0.05). Type IIB MHC decreased from 26.3 ± 1.3% in adult rats to 20.2 ± 1.4% in old animals (P < 0.05). Compared with muscles in adult rats peak isometric tension (Po) tension was decreased 27% in old rats (Table 1) (P < 0.05).
Effects of mechanical load.
Functional overload (OV) increased plantaris mass (Table 1) and CSA (Figure 3) 73% and 72%, respectively, in adult-OV rats (P < 0.05). Plantaris mass and muscle CSA were increased 56% and 69%, respectively in old-OV animals. The CSA of Type I, IIA, and IIX/IIB fibers were increased 46%, 62%, and 58%, respectively, in the adult-OV rats (P < 0.05). Similarly, Type I, IIA, and IIX/IIB fiber CSA increased 62%, 69%, and 69%, respectively, in the aged-OV rats (P < 0.05). Functional overload increased Po 83% and 73%, respectively, in adult-OV and old-OV rats (P < 0.05).
The intent of this study was to determine whether the plantaris muscle of young and aged Fischer 344 (F344) rats undergo similar alterations in muscle mass, fiber CSA, and physiology in response to surgical ablation. Terms such as old and aged have been applied to rats ranging in age from 19 to 38 months of age (1,3,4,28), making direct comparisons of previous research based upon chronological age very difficult. Therefore, probability of survival curves generated by the NIA were employed to ensure that animals used in this study corresponded roughly to humans in their seventh to eighth decade of life. The results of the present study demonstrated little impact of aging on skeletal muscle mass or function and that the hypertrophic response to surgical ablation is not attenuated in very aged F344 rats. Eight weeks after imposition of overload, there was significant plantaris muscle hypertrophy (Table 1) that was reflected by concomitant increases in the average fiber CSA of Type I, IIA, and IIX/IIB fiber types in both adult and old rats (Fig. 3).
Aging was found to have no effect on plantaris muscle mass, average fiber CSA, or the average CSA of the Type I, IIA, and IIX/IIB fiber types. Previous reports examining the age-associated alterations inbred Fischer 344 and Wistar-Car-Hicks rats aged 20–28 months have reported a similar lack of whole muscle or fiber atrophy (8,9). More recently, a significant age-related decline in skeletal muscle mass and fiber CSA have been reported in other rat strains (15), particularly the Fischer 344 x Brown Norway (F1) hybrid rat (1,4).
Aging was found to decrease the ability of the plantaris to generate maximal tetanic tension (Po; N), with no significant decline in maximal specific tension (Po; N·cm−2). A decrease in Po should be related to muscle atrophy, which was not apparent at either the whole muscle (Table 1) or cellular level (Fig. 3). In humans, estimates of maximum specific strength suggest a decrease with age for men (32), and either no change in maximum specific tension for women (31) or a delay in the decline when compared with men of the same age. In the present study, maximal specific tension was ∼15% less in old rats (P < 0.05) when compared with adult animals (Table 1). For muscles from rats, specific tension has been reported to decline (2) or remain unchanged (1,9,12). Eddinger et al. (9) have suggested that the reduction in specific tension seen by others may be due to age-related decrements in neural function rather than muscle atrophy. However, studies, like the present one, in which the muscle was stimulated directly, have failed to demonstrate a decrease in specific tension with aging (12,29). Therefore, the decline in Po and maximal specific tension observed in the present study seem to be unrelated to atrophy.
Muscle plasticity with aging.
In rodents, relatively few experiments have been designed to assess the effect of aging on skeletal muscle hypertrophy. Plantaris muscle hypertrophy resulting from denervation (28) or surgical ablation of synergists (21) was unaffected by age in Sprague-Dawley rats up to 22 months of age. Further, palmaris longus enlargement resulting from resistance training was also unaffected by age in 30 month-old female Sprague-Dawley rats. Consistent with previous research, the present study found an increase in plantaris mass of 42% for the adult animals (1,23). Further, we observed a 36% increase in the plantaris mass of aged rats, which was not different than that found in the adult animals of this study. The lack of an age-associated attenuation in the hypertrophic response is interesting considering that the age of the animals used in the present study corresponded roughly to that of humans in the seventh to eighth decade of life.
Previous research in humans ∼70 yr of age indicates that muscle mass and strength are conserved in individuals who have habitually engaged in resistance training for up to 17 yr (17). However, in humans averaging 87 yr of age, no increase in thigh girth was reported from 10 wk of resistance training (11). We have previously reported marked atrophy and an inability for the plantaris muscle to undergo hypertrophy in 38-month-old Fischer 344 x Brown-Norway (F1) rats (1). The present study utilized very aged F344 rats because of the extensive use of this genotype in aging research. Because the longevity of the F344 rat is much less than the F1 rat, it was not possible to study F344 rats at 38 months of age. However, probability of survival curves indicate that F344 rats at 27 months of age and F1 rats at 38 months of age both have approximately 20% probability of survival. The most striking difference between these models is the lack of age-associated muscle atrophy and dysfunction in F344 rats at 27 months of age. These observations suggests that, in the F344 rat, probability of survival curves may lead to an overestimation of the decline in muscle mass and function with aging. The in-bred F344 rat reduces genetic variability within and between aging rodent studies and has thus served as useful tool in understanding the mammalian aging process (6,9,29). However, recent evidence suggests that other rat genotypes, particularly the F1 hybrid (1,4,20,25) may better model aging processes in skeletal muscle due to a lower incidence and later onset of spontaneous lesions and tumors (6).
Collectively, studies of aging in rodents indicate decreases in fast-twitch characteristics of skeletal muscle including decreases in fast-twitch motor units (21), Type II fiber number and size (4,7,15), and a decrease in fast MHC isoforms (1). In addition, aging rodent skeletal muscle displays decreased Po (1,2,4) and maximal specific tension (1,4), as well as a slowing in tension development and relaxation (4). The above changes in morphology and contractile function precede whole muscle atrophy (3,7,8,28) and appear exacerbated in those studies reporting substantial loss in muscle mass (1,4). Collectively, loss of fast-twitch characteristics and decreased contractile function precede sarcopenia but are exacerbated by loss in muscle mass. Thus, our present observations that aged in-bred Fischer 344 rats do not display muscle atrophy is most likely due to their decreased life expectancy resulting from genetic inbreeding.
In summary, plantaris mass and the CSA of all fiber types were unaffected by age; however, there was a slowing of the MHC composition and decreases in both Po and maximal specific tension in very aged male F344 rats. Furthermore, aging did not attenuate the adaptive response of the plantaris muscle to 8 wk of overload induced by surgical ablation of synergists. Because the age of these animals corresponded roughly to humans in their seventh to eighth decade of life, these data do not support the utility of the F344 rat as a tool to investigate the large age-associated decrements in muscle mass and plasticity seen in very aged humans and rats.
The authors wish to express their appreciation to Miss Erika Mehta for her tireless devotion to animal care during the course of these studies. An Ohio State University Seed Grant provided funding for this research to J. K. Linderman and a Graduate Student Alumni Research Award to E. R. Blough from the Ohio State University Graduate School. The National Institute of Aging graciously provided Fischer 344 rats to E. R. Blough pursuant to dissertation research.
Address for correspondence: J. K. Linderman, The University of Dayton, 40 J Frericks Center, 300 College Park, Dayton, OH 45469-1210; E-mail: firstname.lastname@example.org.
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