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J Appl Physiol 101: 887-892, 2006. First published May 18, 2006; doi:10.1152/japplphysiol.00380.2006
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Effect of aging on the recovery following contraction-induced injury in muscles of female mice

Erik P. Rader and John A. Faulkner

Department of Biomedical Engineering and Institute of Gerontology at the University of Michigan, Ann Arbor, Michigan

Submitted 30 March 2006 ; accepted in final form 11 May 2006


   ABSTRACT
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METHODS
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By the age of 80 yr, the skeletal muscles of men and women decrease in mass and maximum force by ~30%. Severe contraction-induced injury may contribute to these age-related declines. One to two months after a 225 lengthening contraction protocol (LCP), muscles of young/adult male mice recovered completely, whereas those of old male mice sustained deficits of ~15% in mass and ~25% in maximum force. Although gender-related differences in the early events of contraction-induced injury have been reported, the recovery phase of muscles in old female animals has not been investigated. The hypothesis tested was that 2 mo after a severe LCP to the plantar flexor muscle group, the magnitude of recovery of mass and force for old female mice is less than that for adult female mice. The LCP was administered to muscles of adult and old, female C57BL/6 mice. At 3 days, 1 mo, and 2 mo following the LCP, maximum isometric force was measured, and muscles were removed and weighed. Two months following the LCP, the muscles of adult female mice recovered mass and force. In contrast, for old female mice, even after 2 mo, muscle masses were decreased by 11% and maximum forces by 38%. We conclude that, as reported previously for old male mice, a severe contraction-induced injury to muscles of old female mice results in prolonged deficits in mass and force.

plantar flexor muscles; lengthening contractions; sarcopenia

BETWEEN 30 AND 80 yr of age, the skeletal muscles of men and women undergo atrophy and a decrease in force development of ~30% (2, 11, 13, 16, 18). These reductions impair the performance in the activities of daily living and, consequently, impair the quality of life (11). The age-related decreases in mass and force of muscles are largely attributable to the loss of muscle fibers associated with the decrease in the number of motor units (12, 20). Contraction-induced injury following severe lengthening contractions constitutes an additional factor that may contribute to muscle atrophy and weakness of the elderly (5, 21, 25). Contraction-induced injury consists of an initial mechanical disruption of sarcomeres (7, 24, 30) followed by a more severe secondary injury from the infiltration of inflammatory cells and release of reactive oxygen species (24). One to two months following a severe contraction-induced injury to muscles of young/adult male mice, mass and maximum force recovered completely (5, 21, 22, 25). In contrast, the muscles of old male mice sustained deficits of ~15% in mass and ~25% in force (5, 21, 25). These losses exacerbated the age-related structural and functional deficits already present in the muscles.

The effect of gender during the first few days of contraction-induced injury has been studied in muscles of rats (1, 17, 29). For young rats, the extent of initial injury as measured by the loss in force 1 h following a lengthening contraction protocol (LCP) was independent of gender (29). In contrast, during the secondary injury 2–4 days following treadmill running, the muscles of female young rats exhibited less morphological damage than those of male young rats (1, 17). Neither of these studies included measurements of muscle mass or maximum force for the muscles of adult or old female rodents in the months following a severe contraction-induced injury. Consequently, whether the impaired recovery observed previously for muscles of male mice with aging (5, 21, 25) also applies to female mice is not known. We tested the hypothesis that 2 mo after a severe LCP to the plantar flexor muscle group, the magnitude of recovery of mass and force for old female mice is less than that for adult female mice.


   METHODS
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Mice.   Specific-pathogen-free adult (age 6–10 mo) and old (age 25–29 mo) female C57BL/6 mice were obtained from the National Institute on Aging Harlan Sprague Dawley Colony. The mice were housed in a pathogen-free barrier facility in the Unit for Laboratory Animal Medicine at the University of Michigan. Following the LCP, the mice recovered and then remained in a separate barrier facility until they were evaluated at 3 days, 1 mo, or 2 mo afterward. All of the procedures, with exception of histological measurements, were done to the total plantar flexor muscle group, consisting of the gastrocnemius (GTN), plantaris, and soleus muscles, as described previously (25). All procedures were approved by the University of Michigan Committee on the Use and Care of Animals and were in accordance with the Guide for the Care and Use of Laboratory animals [DHHS Publication No. 85-23 (NIH) Revised 1985, Office of Science and Health Reports, Bethesda, MD 20892].

Of the 17 old female mice scheduled to survive for the 1- to 2-mo period after the LCP, 1 mouse died during the first day, 3 mice died during the first month, and 4 mice died during the second month. For control female mice 25–27 mo of age that have not been exposed to a LCP, the expected mortality rate during a 2-mo period is ~25% (26). As a consequence of the high 41% mortality rate following the LCP, only four old mice survived for the evaluations at 1 mo and six old mice survived for the evaluations at 2 mo. Evidently, the LCP administered to the large plantar flexor muscle group stressed the old female mice so severely that the mortality rate was increased almost twofold (25). Of the adult mice evaluated 2 mo after the LCP, three mice had tendons with scar tissue and excessively reduced muscle masses and high deficits in force, values beyond the data of mean ± two standard deviations for the other mice. Severe damage to tendons from surgical procedures, even in the absence of exposure to the LCP, can result in deficits of force as much as 20% (22). Consequently, the data for these three adult mice were excluded from the analyses.

Measurement of maximum isometric force.   Mice were anesthetized with an intraperitoneal injection of 1.3% avertin (0.015 ml/g body wt), and the depth of anesthesia was maintained with additional intraperitoneal injections of 0.1 ml. For each experiment, the mouse was placed on a platform maintained at 37°C, and the distal tendons of the plantar flexor muscle group of the right hindlimb were exposed, kept intact, and clamped to the lever arm of the servomotor (Aurora Scientific). Surface electrodes were placed slightly distal to the knee and around the ankle. The stimulation voltage and subsequently the length of the plantar flexor muscle group were adjusted to produce the maximum isometric twitch force (Pt). After development of Pt, the mean optimal fiber length (Lf) for the plantar flexor muscle group was determined as described in detail previously (25). The frequency of stimulation was increased until maximum isometric tetanic force (Po) had been achieved.

LCP.   Following the measurement of Po, the plantar flexor muscle group was administered the LCP. The muscle group was maximally activated, kept at Lf for 100 ms, stretched at a velocity of 1 Lf/s through a 20% strain relative to Lf, and after stimulation ceased, returned to Lf at the same velocity. The protocol consisted of 225 lengthening contractions, one contraction every 4 s for 5-min bouts with a 5-min rest period between each bout. The Po was measured 1 h after the LCP under the same conditions as those that produced Po before the protocol. The incision at the ankle was sutured closed, and the mouse was allowed to recover until evaluation at 3 days, 1 mo, or 2 mo after the LCP. At the time of evaluation, mice were anaesthetized, and values of Po were measured for the experimental and the contralateral control plantar flexor muscle groups.

Following the measurements of force, the plantar flexor muscles were removed immediately, and the anesthetized mice were euthanized by cervical dislocation. The plantar flexor muscles were blotted dry and weighed. For the contralateral control plantar flexor muscle group, total muscle fiber cross-sectional area (CSA) was estimated as the muscle mass (mg) divided by the product of Lf (mm) and 1.06 mg/mm3 (22). Estimating the CSA based on the same value of density for both age groups is justified because connective tissue constitutes ~5% of CSA for adult and old mice (10) and the change in connective tissue content with aging is so small that no significant change in dry mass-to-wet mass ratio of muscle is observed with aging (4). Specific Po (kN/m2) was calculated as the Po (mN) divided by the CSA (mm2).

Histological analyses.   Histological measurements were limited to the GTN muscle because analysis of the entire plantar flexor muscle group was not practical as a consequence of the variability introduced by assessing multiple muscles of different architecture and the number of fibers for the muscle group, ~12,000 (25). Immediately after, the GTN muscle was surgically removed and weighed, and the muscle was covered with tissue-freezing medium, frozen in cold isopentane, and stored at –80 °C. The midbelly of each muscle was cryosectioned at a thickness of 12 µm and then stained with hematoxylin and eosin. All of the fibers for each section were analyzed using the Bioquant image-analysis software package (Bioquant Imaging System, Nashville, TN). Damaged fibers were defined as those with infiltration of inflammatory cells and disruption or disappearance of contractile material (30). For muscles administered the LCP, the percentage of damaged fibers in GTN muscles 3 days after the injury protocol was estimated by dividing the number of damaged fibers by the total number of fibers in the section of the muscle.

Three days following the LCP, no evidence of regeneration was observed in the transverse sections. In contrast, 1–2 mo after the LCP, central nucleated fibers were apparent. Consequently, 30% of the fibers in a section of each GTN muscle were selected and analyzed for fibers with central nuclei. Each cross section was viewed at x45magnification with ~90 frames required to observe the entire section. An image was acquired for every third frame using the Bioquant system. Central nucleated fibers were defined as those with cytoplasm between any of the observable nuclei and the plasma membrane. The percentage of muscle fibers with central nuclei was calculated by dividing the number of central nucleated fibers by the total number of fibers with at least one nucleus visible. The difference between these percents for contralateral control and injured muscles of each mouse was used to determine the extent of central nucleation beyond that of control levels.

Statistical analyses.   All data are expressed as means ± SE. The data for body masses and forces 1 and 3 days after the LCP were not normally distributed and, therefore, were analyzed by the Mann-Whitney ranked-sum test. Data for contralateral control muscle groups and muscle groups 1 h and 3 days following exposure to the LCP were analyzed by one-tailed Student’s t-tests. The percentages of fibers with central nuclei in contralateral control and LCP-exposed muscles and the extent of central nucleation that exceeded control levels were analyzed with a two-way analysis of variance accounting for the age and time allowed for recovery. The data for the recovery of muscle mass and force 1–2 mo following the LCP were analyzed using a two-way analysis of variance with the two factors as age and time allowed for recovery. Differences between age groups at 1 and 2 mo were assessed with one-tailed Student’s t-tests with Bonferroni adjustment. Significance for each statistical test was set a priori at P ≤ 0.05.


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Contralateral control muscles.   The body masses of 25.8 ± 0.8 g for adult and 25.7 ± 0.7 g for old female mice were not different. Compared with the contralateral control plantar flexor muscle groups of adult mice, those of old mice had values of mass 23% less and CSA 21% less (Table 1). The reduced mass and CSA with aging were accompanied by decreases of 35% for Po and 18% for specific Po (Table 1). For old mice, the percentage of central nucleated fibers in contralateral control GTN muscles increased fourfold compared with that of adult mice (Table 2, Fig. 1).


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  		Table 1. Muscle mass, Lf, CSA, Po, and specific Po for contralateral control plantar flexor muscle groups of adult and old female mice

 

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  		Table 2. Following a 225 lengthening contraction protocol, the muscle mass and Po values of plantar flexor muscle groups and the raw data to determine the percentages of central nucleated fibers of gastrocnemius muscles

 

Figure 1
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  		Fig. 1. Percentages of fibers with central nuclei in contralateral control gastrocnemius muscles and gastrocnemius muscles 1 and 2 mo after exposure to the lengthening contraction protocol (LCP). Values are means ± SE; n = 9–12 per value. The contralateral control levels were subtracted from the data for the muscles exposed to the LCP to estimate the extent of central nucleation as a consequence of the LCP and beyond that of control levels. Data at 1 and 2 mo were able to be pooled because no differences in values at those time points were observed. *Different from value for adult mice, P ≤ 0.05.

 
Magnitude of injury 1 h and 3 days following the LCP.   One hour and 3 days after the LCP, no differences between the age groups were observed for the decrease in force, edema, or fiber damage. One hour following the LCP, the values of Po for plantar flexor muscle groups of adult mice were 23 ± 2% of preinjury Po and those of old mice were 25 ± 4%. Three days post-LCP, values of Po were 27 ± 5% for adult mice and 31 ± 9% for old mice, and muscle masses were 114 ± 6% of the contralateral control masses for adult mice and 121 ± 7% for old mice. At 3 days, for adult mice, 19 ± 5% of fibers were damaged (739 ± 290 fibers from a total of 3,512 ± 585 fibers damaged) (Fig. 2). For old mice, 22 ± 4% of the fibers were damaged (639 ± 143 of a total of 3,227 ± 569 fibers injured). These data demonstrated a severe contraction-induced injury to the plantar flexor muscle group with no differences in the magnitude of injury between age groups in the initial days following the LCP.


Figure 2
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  		Fig. 2. Transverse sections of lateral gastrocnemius muscles from female mice; contralateral muscles from adult (A) and old (B) mice, muscles 3 days after lengthening contractions from adult (C) and old (D) mice, and muscles 2 mo after lengthening contractions from adult (E) and old (F) mice. Sections were stained with hematoxylin and eosin. Bar = 100 µm.

 
Recovery 1 and 2 mo following the LCP.   Based on the analysis of variance, the recovery of muscle mass and force and the percentage of fibers with central nuclei that exceeded control levels were dependent on age. The recovery of muscle mass was also dependent on the time allowed for recovery. One month after the LCP, no difference between age groups was observed between the values of Po expressed as a percentage of preinjury Po, 75 ± 8% for adult mice and 56 ± 11% for old mice. Two months post-LCP, forces for muscle groups of adult mice were not different from preinjury values, whereas those of old mice remained at 62 ± 11% of preinjury values (Fig. 3A). The magnitude of recovery for muscle mass of each age group was consistent with the data regarding force. One month following the LCP, the masses of the muscle groups were not different between the age groups, 87 ± 2% of contralateral control masses for adult mice and 81 ± 4% for old mice. Whereas the masses of plantar flexor muscle groups for adult mice returned to control values by 2 mo post-LCP, the muscle groups of old mice remained atrophied at 89 ± 3% of contralateral control values (Fig. 3B). Because the percentage of central nucleated fibers was independent of the time allowed for recovery, the data at 1 and 2 mo were pooled for each age group (Table 2, Fig. 1). For the muscles 1–2 mo following the LCP, no differences in the percentages of fibers with central nuclei were observed between age groups (Fig. 1). In contrast, when contralateral control levels of central nucleation were subtracted from those of the injured muscles, the value for muscles of old mice, 49 ± 4%, was less than that for adult mice, 58 ± 2% (Fig. 1).


Figure 3
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  		Fig. 3. Force [maximum isometric tetanic force (Po); A] and mass (B) values for plantar flexor muscle groups of adult and old female mice 1 and 2 mo after the LCP. Values are means ± SE. One month following the LCP, n = 5 per value with the exception of the data for old mice, n = 3–4, as a consequence of the high mortality rate. At 2 mo, n = 6–7 per value. *Different from value for adult mice at that time period, P ≤ 0.05.

 

   DISCUSSION
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Previous reports of a severe contraction-induced injury to small non-weight-bearing (5, 21) and large weight-bearing muscles (25) of male mice concluded that damage to skeletal muscle fibers contributed significantly to the age-related declines in muscle mass and maximum force. We now report that 2 mo following a severe LCP, the large weight-bearing plantar flexor muscle groups of the adult female mice recovered mass and force completely and in a manner consistent with that of their male counterparts (25). For old female mice, the degree of age-related muscle atrophy and loss in force present without exposure to the LCP and the LCP-induced deficits were not different from the values for old male mice (5, 21, 25). Whether any additional recovery of mass or force occurred after the 2-mo period for the muscles of the old female mice is beyond the scope of this study. Clearly, the recovery of the muscles of the old female mice was impaired compared with that of the adult female mice. We conclude that regardless of gender, the muscle mass and force developed by muscles of adult mice return to control values following a severe contraction-induced injury, whereas those of old mice suffer prolonged losses in muscle mass of 11–20% and maximum force of 20–40% that contribute to the age-related deficits in mass and force already present in muscles of old mice (present study; Refs. 5, 21, 25).

The finding that the magnitude of injury for muscles of female mice was in good agreement with that of age-matched male mice from a previous report (25) is in contrast with the observations of other studies (1, 17). The lack of gender-related differences following the 225 LCP was likely a consequence of the severity of the protocol. The reduced morphological damage observed previously for muscles of young female rats compared with that of young male rats occurred several days following downhill treadmill running, a much less severe protocol than the LCP used in the present study (1, 17). Following treadmill running to muscles of rats (28) or an in vivo LCP to muscles of mice (27), the inflammatory response was reduced for the females compared with that of the males. Whether differences in the inflammatory response occurred for the present study was not determined. What is apparent is that the severe LCP injured the muscles of adult and old female mice to such a degree that any effects of gender on inflammation were insufficient to cause the recovery to differ from that of age-matched male mice (5, 21, 25).

For the injured muscles 1–2 mo following the severe LCP, the percentage of fibers with central nuclei, ~60%, was independent of age. One interpretation of this finding is that the regeneration processes following the LCP were unaltered by aging and did not limit the recovery of the muscles for old female mice. Under these circumstances, an age-related increase in the severity of injury to individual muscle fibers may have accounted for the age-related differences in muscle mass and force 2 mo following the LCP. Despite the similar deficits in force at the whole muscle level 3 days post-LCP for both age groups, at the level of single fibers, the specific characteristics of the injury may have differed. In a previous report regarding single muscle fibers of rats (6), fibers of old rats were more susceptible to contraction-induced injury than those of young/adult rats. A severe injury to muscle fibers of old mice might well result in necrosis, which would account for the sustained deficits in muscle mass and force (5, 21, 25).

An alternate interpretation of the data regarding central nuclei is possible. For muscles of old female mice 1–2 mo following the LCP, the presence of some of the central nuclei may have been independent of the exposure to the LCP. To estimate the extent of central nucleation as a response exclusively to the LCP, the contralateral control levels of central nucleation were subtracted from the levels for injured muscles. The resulting percent for old mice, ~50%, was less than that for adult mice, ~60%. This observation for old mice may be the consequence of impaired initial regeneration of injured muscle fibers (9) or the loss of fibers that began regenerating but failed to survive because of a lack of innervation or other form of trophic support (23). An impaired initial regenerative process consisting of a failure of myotube formation was observed in muscles of old mice 5 days following injury by exposure to dry ice (9). In a study of minced muscles, fibers of mice were able to begin regeneration but in the absence of innervation disappeared by 3 wk (23). Regardless of the underlying mechanism, an impaired regeneration for the muscles of old female mice may be a consequence of innervation or systemic factors rather than satellite cell population (8, 9). Muscles from old animals regenerate as well as those from young animals when grafted into a young host (8) or exposed to the circulatory system of a young animal (9).

For elderly women, the benefits of moderate conditioning protocols have been demonstrated clearly (14, 19). Despite the possibility of long-term damage to skeletal muscles, the elderly are encouraged to perform training regimes that consist of lengthening contractions because of the potential of such regimes to maintain bone mass and strengthen muscles (14, 15, 19) and reduce the risk of falls (3). Regardless of gender, such training protocols must be designed and implemented with the utmost care and consideration of the potential of the lengthening contractions to cause prolonged deficits in mass and force (present study, 5, 21, 25).


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This research was supported by Contractility Core of the Nathan Shock Center Grant P30 AG-13283 and National Institute on Aging (NIA) Grant AG-20591. E. Rader was supported by a fellowship awarded by the Whitaker Foundation, NIA Training Grant T32 AG-00114-18, and Regenerative Sciences Training Grant T90 DK-070071.


   FOOTNOTES
 

Address for reprint requests and other correspondence: J. A. Faulkner, Institute of Gerontology, Univ. of Michigan, Ann Arbor, MI 48109-2200 (e-mail: jafaulk{at}umich.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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