Eur J Appl Physiol (2009) 107:489–499 DOI 10.1007/s00421-009-1136-0

ORIGINAL ARTICLE

Differential atrophy of the lower-limb musculature during prolonged bed-rest Daniel L. Belavy´ Æ Tanja Miokovic Æ Gabriele Armbrecht Æ Carolyn A. Richardson Æ Jo¨rn Rittweger Æ Dieter Felsenberg

Accepted: 15 July 2009 / Published online: 13 August 2009 Ó Springer-Verlag 2009

Abstract Patients with medical, orthopaedic and surgical conditions are often assigned to bed-rest and/or immobilised in orthopaedic devices. Although such conditions lead to muscle atrophy, no studies have yet considered differential atrophy of the lower-limb musculature during inactivity to enable the development of rehabilitative exercise programmes. Bed-rest is a model used to simulate the effects of spaceflight and physical inactivity. Ten male subjects underwent 56-days of bed-rest. Magnetic resonance imaging of the lower-limbs was performed at 2-weekly intervals during bed-rest. Volume of individual muscles of the lower-limb and subsequently, rates of atrophy were calculated. Rates of atrophy differed (F = 7.4, p \ 0.0001) between the muscles with the greatest rates of atrophy seen in the medial gastrocnemius, soleus and vastii (p \ 0.00000002). The hamstring muscles were also affected (p \ 0.00015). Atrophy was less in the ankle dorsiflexors and anteromedial hip muscles (p [ 0.081). Differential rates of atrophy were seen in synergistic muscles (e.g. adductor magnus [ adductor longus, p = 0.009; medial gastrocnemius [ lateral gastrocnemius, p = 0.002;

D. L. Belavy´ (&)  T. Miokovic  G. Armbrecht  D. Felsenberg Centre for Muscle and Bone Research, Charite´ Campus Benjamin Franklin, Free University and Humboldt-University Berlin, Hindenburgdamm 30, 12200 Berlin, Germany e-mail: [email protected] C. A. Richardson School of Health and Rehabilitation Sciences, The University of Queensland, Brisbane, QLD 4072, Australia J. Rittweger Institute for Biomedical Research into Human Movement and Health, Manchester Metropolitan University, Manchester M1 5GD, UK

vastii [ rectus femoris, p = 0.0002). These results demonstrate that muscle imbalances can occur after extended periods of reduced postural muscle activity, potentially hampering recovery on return to full upright body position. Such deconditioned patients should be prescribed ‘‘closedchain’’ simulated resistance exercises, which target the lower-limb antigravity extensor muscles which were most affected in bed-rest. Keywords Berlin Bed Rest Study  Magnetic resonance imaging  Microgravity  Muscle atrophy

Introduction Patients with many medical conditions are prescribed bedrest and/or immobilised in orthopaedic devices to decrease muscle function through the lower-limb in order to protect healing tissue. Such patients may be, for example, subject to bed-rest with limb-traction for bone fractures, recovering on medical wards after a prolonged stay in intensive care, mobilising on orthopaedic wards after joint replacement, confined to bed on ante-natal wards due to medical complications arising during pregnancy (e.g. Gupton et al. 1997), or beginning full weight-bearing as part of rehabilitation after a sports-related injury to the lower-limb, with subsequent immobilisation and crutch use. Whilst in some of these instances, muscle atrophy may be expected as a result of the injury itself, little information is available in the scientific literature as to the effects of inactivity on the patterns of muscle atrophy in the lower-limb. Prolonged bed-rest in healthy subjects is a model used by space-agencies to simulate the effects of spaceflight (Pavy-Le Traon et al. 2007). This permits the study of

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changes in musculoskeletal function caused by a lack of weight-bearing through the lower-limb during functional upright activities (i.e. standing, walking and running), without pain and/or injury. Aside from deepening our understanding of muscle function and dysfunction in the lower-limb, such information would also guide the design of remedial exercise programmes suitable for the deconditioned patient or inactive individuals. Clinical intuition would suggest that the extensor muscles of the knee and ankle would be most affected during bed-rest, as it is these that are important in maintaining our upright stance under earth’s gravitational field. Indeed, data from bed-rest studies suggest this to be the case, with, for example very strong effects for losses in muscle volume during bed-rest seen in the plantarflexor muscles of the ankle, but little change in the dorsiflexors (e.g. Akima et al. 2001). It seems also that individual muscles within synergistic groups (e.g. soleus compared to gastrocnemius, Akima et al. 2000; and the vastii compared to rectus femoris, Alkner and Tesch 2004b) may be more affected due to inactivity. This hypothesis can be drawn from the current literature showing, for example, significant changes in muscle size in one muscle, but not in its synergist. Unfortunately, however, in all of the works in bed-rest that we have identified (Akima et al. 2000, 2001, 2007; Alkner and Tesch 2004a, b; Berry et al. 1993; Cao et al. 2005; Kouzaki et al. 2007; Le Blanc et al. 1988, 1992; Shackelford et al. 2004; Zange et al. 2008), none have performed direct tests comparing the relative amounts of atrophy between muscles of the lower-limb, to show whether the amounts, or rates, of atrophy do indeed differ. Understanding the pattern of muscle atrophy in the lower-limb during inactivity would be highly relevant in guiding our management of the deconditioned patient; and notwithstanding, guide the rehabilitation of astronauts. The aim of this study was to examine the rate of atrophy in the individual lower-limb muscles during prolonged bed-rest of an 8-week duration. In order to investigate whether differing muscles of the lower-limb show differential rates of atrophy, multiple measurements of muscle size (ideally, muscle volume) are needed to examine the time course of muscle atrophy throughout the bed-rest period.

Methods Bed-rest protocol The ‘‘Berlin Bed-Rest Study’’ was undertaken at the Charite´ Campus Benjamin Franklin Hospital in Berlin, Germany, from February 2003 to June 2005. Ten male subjects

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(33.4[6.6] years, 185[7] cm, 79.4[9.7] kg; mean[SD]) underwent 8 weeks of strict bed-rest. The bed-rest protocol, as well as inclusion and exclusion criteria, is discussed in detail elsewhere (Rittweger et al. 2006). In brief, however, horizontal bed-rest was employed, though subjects were permitted to be positioned in up to 30° head-up tilt for recreational activities during daylight hours (such as watching television). Subjects performed all hygiene in the supine position and were discouraged from moving excessively or unnecessarily. Force sensors placed in the bed supports, 24-h nursing care and video surveillance permitted monitoring of subjects’ activities. The institutional ethics committee approved this study and subjects gave their informed written consent. Subjects were aware that their participation in the study was voluntary and that they were permitted to withdraw from the study at any time. Magnetic resonance imaging protocol Baseline magnetic resonance (MR) scanning was conducted on the first day of bed-rest (BR1) and then at 2-week intervals (BR14, BR28, BR42 and BR56) through to the end of the bed-rest period. Subjects were positioned on the scanning bed in supine with their knees and hips supported in slight flexion by a pillow under the knee. Transverse MR images were acquired, using a 1.5 Tesla Magnetom Vision system (Siemens, Erlangen, Germany) from the lowerlimbs. Typically, 35 images of the thigh (from the superior aspect of the head of femur to the knee joint line; thickness = 10 mm, inter-slice distance = 5 mm, TR = 6,000 ms, TE = 15 ms, FA = 180°, field of view: 480 9 480 mm interpolated to 512 9 512 pixels) and 30 images of the lower-leg (knee joint line to the distal most portion of the lateral malleolus; thickness = 10 mm, inter-slice distance = 5 mm, TR = 4,800 ms, TE = 15 ms, FA = 180°, field of view: 340 9 340 mm interpolated to 512 9 512 pixels) were acquired, though for taller subjects, additional images were added to ensure the region of interest was captured. Images were stored for offline analysis. Image measurements One operator (TM) performed all image measurements. As the right leg was tested in other experiments involving leg muscle isometric contraction (Mulder et al. 2006) or knee movement (Belavy´ et al. 2007) during the bed-rest phase, only the left leg was considered in analyses. To ensure operator blinding to study time-point and subject group, each dataset was assigned a random number (http://www. random.org). ImageJ (Ver. 1.38x, http://rsb.info.nih.gov/ij/) was used for MR image analysis. Cross sectional area (CSA) of the following muscles in the thigh (Fig. 1) were measured in each image: rectus femoris (RF), vastii (V),

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Fig. 1 Thigh muscle image measurements. Example images from the upper (left) and lower (right) thigh. Thirty-five images were acquired from the superior aspect of the femoral head to the knee joint line. The crosssectional area (when present) of the muscles, rectus femoris (RF), vastii (V), sartorius (SART), gracilis (GRAC), adductor magnus (AM), adductor longus (AL), biceps femoris long head (BFL), biceps femoris short head (BFS), semitendinosus (SEMI_T) and semimembranosus (SEMI_M) was measured in each image

sartorius (SART), gracilis (GRAC), adductor magnus (AM), adductor longus (AL), biceps femoris long head (BFL), biceps femoris short head (BFS), semitendinosus (SEMI_T) and semimembranosus (SEMI_M). Whilst AM and AL could be readily differentiated from adductor brevis, this adductor muscle could not easily be differentiated from pectineus and hence was not measured. In the lower leg (Fig. 2) the following muscles were measured: gastrocnemius lateralis (GLAT), gastrocnemius medialis (GMED), soleus with flexor hallucis longus (SOL; as too few anatomical landmarks (e.g. fascia) were available on MRI, soleus was difficult in a number of subjects to separate from flexor hallucis longus. The results of the current study do not change when soleus is considered separately from flexor hallucis longus, thus the data presented is pooled from both muscles), tibialis posterior (TIBP), flexor digitorum longus (FDL), peroneal group (PER; peroneus longus, brevis and tertius), anterior tibial muscles (ANT; tibialis anterior, extensor digitorum longus, extensor hallucis longus). A total of 17,192 individual manual CSA measurements comprised the final dataset, requiring approximately 430 person-hours for analysis. Further data processing To efficiently check for any errors in image measurement, another operator (DLB), also blinded to study time-point and subject group, plotted data from each muscle for every scanning date for a particular subject (Fig. 3). To enable assessment of changes in entire muscle volume, individual CSA measurements for each muscle were interpolated with the following equation:  n  X CSA Slicei þ CSA Sliceiþ1  1:5 cm ð1Þ 2 i¼1 where n represents the number of images in a dataset. The 1.5 cm conversion factor comprised an image thickness of

1.0 cm and inter-image distance of 0.5 cm. The resulting muscle volume data was used in further analyses. Given that muscle is of a finite size and a negative muscle volume is not possible, it would be invalid to assume a linear model of muscle atrophy and a model of exponential decay would be most appropriate (e.g. Booth 1977). Therefore, in order to examine whether rates of muscle volume loss varied in the differing muscles of the leg and thigh due to inactivity, the data from each subject was normalised to its baseline value with the formula: (volumeBRx - volumeBR1)/volumeBR1 (where BRx represents any given scanning date) such that ‘‘1’’ represented the baseline value and ‘‘0’’ would represent complete loss of muscle volume (see Fig. 4). If baseline data was missing for a particular subject, then this subject was excluded from this aspect of the analysis. Statistical analyses A non-linear mixed-effects model (Pinheiro and Bates 2000) was used to fit an exponential decay model e(k(BRx-1)) (where k is the time constant for muscle volume loss and BRx is day x of bed-rest, such that at baseline (BR1) e(k(BRx-1)) = ‘‘1’’) to the muscle volume data normalised to baseline volume (i.e. baseline volume = ‘‘1’’). Fixed effects for muscle (RF, V, SART, GRAC, AM, AL, BFL, BFS, SEMI_T, SEMI_M, GLAT, GMED, SOL, TIBP, FDL, PER and ANT) and random effects for each subject and muscle within subject were modelled. Allowances were made for heterogeneity of variance between muscles and study-date. Subsequent analysis of variance (ANOVA) was tested for significance of variation of time constant estimates between muscle; where ANOVA suggested differences between muscles in rates of volume loss, post-hoc contrasts between each muscle pair evaluated the significance of the differences in the time constant estimates between individual muscles.

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Fig. 2 Lower leg muscle image measurements. Example images from the upper (left) and lower (right) calf. Thirty images were acquired from the knee joint line to the lateral malleolus. The crosssectional area (when present) of the muscles, gastrocnemius lateralis (GLAT), gastrocnemius medialis (GMED), soleus with flexor hallucis

longus (SOL; in this subject flexor hallucis longus, FHL, is shown separately), tibialis posterior (TIBP), flexor digitorum longus (FDL), peroneals (PER; peroneus longus, brevis and tertius) and anterior tibial (ANT; tibialis anterior, extensor digitorum longus, extensor hallucis longus) was measured in each image

Fig. 3 Example dataset showing reduction in vastii muscle size in one subject To enable efficient assessment of muscle cross-sectional area measurements, data points (in cm2) from each individual subject were plotted for each muscle (in this example the vastii muscle group) across all scanning dates. Whilst the operator was blinded to scanning date and group allocation, for the convenience of the reader, the scanning time points are indicated in the plot legend. BR1, BR14,

BR28, BR42, BR56 = 1st, 14th, 28th, 42nd and 56th days of bedrest, respectively. The measurement from BR42 is shifted slightly to the left (towards femoral head) due to slightly different positioning of the scanning region on that day; however, the entire volume of the muscle was captured. Note the progressive loss of overall muscle size (as assessed by the area under the curve) over the course of bed-rest

All analyses were performed in the ‘‘R’’ statistical environment (version 2.4.1, http://www.r-project.org). An a of 0.05 was taken for statistical significance. As multiple imaging sessions were undertaken on the same subjects, we looked for consistent significant differences across time points.

To better understand the observed outcomes of the study, further analyses were performed in relation to anatomical, functional and morphological variables of the individual muscles. Muscle were classified as either ‘‘biarticular’’ (gastrocnemius lateralis and medialis, peroneals, biceps femoris long head, semitendinosis, semimembranosus,

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493 Table 1 Number of datasets available for analysis on each study-date Study-date

N Leg

Thigh

BR1

8a

6a,b

BR14

10

10

BR28

10

9b

BR42

10

10

BR56

10

10

BR day of bed-rest

Fig. 4 Calculation of rates of muscle volume loss. Data points are proportional change compared to baseline (=‘‘1’’) of muscle volume over the course of the study in the gastrocnemius medialis muscle. As part of statistical modelling, an exponential decay model was fitted to the proportional change in muscle volume and the time constant muscle volume loss calculated. See text for further details

flexor digitorum longus, anterior tibial muscles, gracilis, rectus femoris, sartorius) or ‘‘monoarticular’’ (soleus, tibialis posterior, adductor magnus, biceps femoris short head, vastii, adductor longus) on an anatomical basis and also as ‘‘anti-gravity’’ (soleus, gastrocnemius medialis and lateralis, peroneals, tibialis posterior, adductor magnus, biceps femoris long head, biceps femoris short head, semimembranosus) or ‘‘other’’ (flexor digitorum longus, anterior tibial muscles, adductor longus, gracilis, rectus femoris, sartorius). Further exponential decay models e(k(BRx-1)) were then fitted with non-linear mixed-effects models similar to the analyses for the individual muscles but that factors of anatomical-type (mono- or biarticular) and functional-type (anti-gravity or other) as well as interactions between the two factors were considered. Also, an attempt was made to examine the relationship of the rates of volume loss (k) to known morphological and histological characteristics of the muscles. Spearman’s correlation coefficient (q) was calculated between ‘‘k’’ and baseline muscle volume as well as relative proportions of muscle spindles (from Voss 1971) and percentages of type I muscle fibres (from Johnson et al. 1973 and Edgerton et al. 1975) in each muscle. Correlations with other morphological variables (e.g. pennation angle) were not possible as normative data in the literature were only available for a restricted number of muscles.

Results Due to issues, such as movement artefacts or scanner failure, datasets were not available for analysis for all subjects from every scanning session. Table 1 lists the number of datasets available for analysis. Table 2 shows the volume of each of the muscles at the start of bed-rest

a

Two datasets missing due to MRI scanner failure

b

Scanning performed but data not appropriate for analysis

and their percentage change after 2-weeks of bed-rest (BR14) and beyond. Rate of muscle volume loss during bed-rest Fitting of models of exponential decay to the relative changes in muscle volume during bed-rest compared to baseline (BR1) showed that the overall rate (time constant estimate) of volume loss was non-zero (intercept term in ANOVA: F1,322 = 29.2, p \ 0.0001; indicating that significant decreases in muscle volume occurred overall) and that the rates of atrophy differed strongly between muscles (muscle: F16,322 = 8.81, p \ 0.0001; Fig. 5 and Table 3). The fastest rates of atrophy were seen in the medial gastrocnemius, the rate of atrophy of which was marginally faster than the vastii (p = 0.0502 vastii vs. medial gastrocnemius; Table 3) and the soleus muscle (p = 0.0305 soleus vs. gastrocnemius; Table 3). The medial hamstrings (semitendinosus and semimembranosus), biceps femoris long head and lateral gastrocnemius all showed similar rates of atrophy, which were marginally (i.e. not significantly) slower than the other heads of triceps surae and the vastii. The tibialis posterior, the peroneal muscle group and adductor magnus also showed significant time constants (all p \ 0.0014). Interestingly, in contrast to the findings in adductor magnus, the other members of the medial thigh musculature (adductor longus, gracilis and sartorius), did not show significant rates of atrophy during bed-rest (all p [ 0.081) and adductor magnus atrophied at a significantly greater rate than adductor longus (p = 0.0085 adductor longus vs. adductor magnus; Table 3). Finally, no evidence existed (all p [ 0.105) for significant rates of atrophy in the ankle dorsiflexors and toe extensors (anterior tibial muscles), the toe flexors (flexor digitorum longus) and rectus femoris. Relationship of rates of atrophy to functional, morphological and histological muscle characteristics The rates of atrophy were strongly dependent upon the functional-type of the muscles (F = 53.4, p \ 0.0001)

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Table 2 Baseline muscle volume and percentage changes during bed-rest Muscle

Study-date BR1 (cm3)

BR14 (%)

BR28 (%)

BR42 (%)

BR56 (%)

Anterior tibial muscles

256.1 (5.1)

-0.7 (1.5)

-0.8 (1.4)

-1.2 (1.5)

Flexor digitorum longus

30.7 (2.5)

?2.9 (1.3)*

-4.1 (2.1)

-2.3 (1.6)

Peroneals

143.5 (9.4)

-1.4 (1.6)

-4.3 (2.0)*

-7.5 (1.9)***

-10.8 (2.2)***

Tibialis posterior

112.9 (7.4)

-4.2 (1.5)**

-6.1 (1.7)***

-6.2 (1.5)***

-10.2 (1.7)***

Soleus with FHL

589.9 (22.2)

-6.2 (1.8)**

-9.1 (1.8)***

-12.3 (1.8)***

-16.5 (1.8)***

Gastronemius lateralis

150.5 (9.5)

-7.7 (3.8)*

-11.2 (2.9)***

-10.5 (1.8)***

-14.4 (2.8)***

Gastrocnemius medialis Adductor longus

229.7 (16.8) 181.7 (11.8)

-9.4 (1.5)*** ?2.7 (3.7)

-13.8 (1.6)*** ?0.4 (3.6)

-18.1 (1.1)*** ?0.5 (3.2)

-22.3 (1.5)*** ?0.8 (3.1)

Adductor magnus

588.7 (22.5)

-5.1 (2.8)

-5.0 (3.6)

-6.2 (2.3)*

-7.0 (2.6)*

Gracilis

118.4 (7.0)

-2.9 (2.2)

-2.7 (2.3)

-4.0 (2.2)

-4.4 (2.2)*

Sartorius

177.7 (10.1)

-3.8 (3.0)

-0.7 (3.0)

-2.1 (2.7)

-4.9 (3.3)

Biceps femoris long head

232.8 (16.1)

-5.2 (5.6)

-6.7 (5.6)

-10.2 (5.5)

-12.5 (5.5)*

Biceps femoris short head

123.7 (8.4)

-3.8 (3.1)

-2.1 (3.0)

-3.3 (2.7)

-7.3 (3.0)*

Semimembranosus

273.6 (11.5)

-6.5 (2.4)**

-6.5 (2.4)**

Semitendinosus

250.1 (16.8)

-6.5 (4.9)

-7.6 (4.9)

-8.7 (4.9)

Rectus femoris

318.2 (19.8)

-4.1 (3.5)

-2.7 (3.5)

-2.9 (3.4)

1914.5 (83.1)

-6.7 (3.7)

-9.9 (3.6)**

Vastii

-11.1 (1.4)***

-13.3 (3.5)***

-5.1 (1.7)** -8.7 (1.8)***

-12.3 (1.3)*** -10.4 (4.9)* -5.1 (3.5) -15.9 (3.7)***

At 1st day of bed-rest (BR1) values are mean (SEM) muscle volume in cm3. Beyond BR1 values are mean (SEM) percentage change compared to BR1. *p \ 0.05; **p \ 0.01; ***p \ 0.001 and indicate significance of difference to baseline value. BR day of bed-rest, FHL flexor hallucis longus muscle. Anterior tibial muscles comprise the tibialis anterior, extensor digitorum longus and extensor hallucis longus muscles

Fig. 5 Estimates of rates of volume loss (exponential rates of decay) in the lower-limb muscles. Values are mean (error bars: SEM) estimates of the time constant k in the fitted exponential decay model e(k (BRx-1)) (where BRx is the xth day of bed-rest). More negative time constants indicate faster loss of muscle volume during bed-rest. ANT: anterior tibial muscles (tibialis anterior, extensor digitorum longus, extensor hallucis longus), FDL: flexor digitorum longus, PER: peroneals (peroneus longus, brevis and tertius), TIBP: tibialis posterior, GLAT: gastrocnemius lateralis, SOL: soleus with flexor

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hallucis longus, GMED: gastrocnemius medialis, RF: rectus femoris, V: vastii, SART: sartorius, GRAC: gracilis, AM: adductor magnus, AL: adductor longus, BFL: biceps femoris long head, BFS: biceps femoris short head, SEMI_T: semitendinosus, SEMI_M: semimembranosus. p \ 0.01; p \ 0.001 and indicate significance of the time constant mean compared to zero. Otherwise p [ 0.05. See Table 3 for the significance of differences between muscles in rates of volume loss

0.30

0.21

0.10

0.10

0.08

0.009

0.003

0.002

0.002

0.000 <0.0001

<0.0001

<0.0001

<0.0001

<0.0001

FDL

RF

BFS

GRAC

AM

PER

TIBP

SEMI_T

BFL GLAT

SEMI_M

SOL

V

GMED

<0.0001

<0.0001

<0.0001

0.0003

0.001 0.0004

0.006

0.028

0.032

0.080

0.39

0.44

0.45

0.77

0.79

ANT

<0.0001

0.0001

0.0001

0.001

0.006 0.003

0.076

0.020

0.09

0.15

0.58

0.63

0.65

0.56

SART

<0.0001

<0.0001

<0.0001

0.0007

0.003 0.001

0.056

0.014

0.06

0.17

0.56

0.62

0.64

FDL

<0.0001

0.0002

0.0004

0.0034

0.014 0.007

0.16

0.049

0.19

0.32

0.91

0.95

RF

<0.0001

0.0004

0.001

0.0064

0.024 0.013

0.21

0.07

0.23

0.40

0.96

BFS

<0.0001

0.0002

0.0006

0.0047

0.019 0.010

0.20

0.06

0.22

0.38

GRAC

<0.0001

0.003

0.006

0.004

0.11 0.064

0.29

0.63

0.72

AM

<0.0001

0.011

0.018

0.08

0.23 0.15

0.94

0.50

PER

<0.0001

0.015

0.024

0.10

0.27 0.18

0.56

TIBP

0.0001

0.064

0.10

0.27

0.59 0.46

SEMI_T

0.001

0.20

0.28

0.55

0.85

BFL

0.002

0.27

0.36

0.68

GLAT

0.015

0.54

0.67

SEMI_M

0.031

0.85

SOL

0.050

V

Values are p-values of direct comparisons between muscles of estimates of rates of volume loss. Strongly significant (p \ 0.01) differences are in bold. ANT anterior tibial muscles (tibialis anterior, extensor digitorum longus, extensor hallucis longus), FDL flexor digitorum longus, PER peroneals (peroneus longus, brevis and tertius), TIBP tibialis posterior, GLAT gastrocnemius lateralis, SOL soleus with flexor hallucis longus, GMED gastrocnemius medialis, RF rectus femoris, V vastii, SART sartorius, GRAC gracilis, AM adductor magnus, AL adductor longus, BFL biceps femoris long head, BFS biceps femoris short head, SEMI_T semitendinosus, SEMI_M semimembranosus. See Fig. 4 for estimates of rates of atrophy

0.36

SART

AL

ANT

Muscle

Table 3 Comparisons of rates of muscle atrophy in the lower-limb muscles

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Table 4 Correlations between rates of atrophy and morphological and histological muscle characteristics Spindle proportiona Type I percentageb Volumec Rate of atrophy 0.593*

0.018

-0.358

Values are Spearman’s correlation coefficient. *p = 0.02; otherwise p C 0.15 a

Values taken from Voss (1971). Where data for individual muscles (i.e. medial/lateral gastrocnemius and biceps femoris long/short heads) were not available, rates of atrophy (k) were recalculated for the combined muscle (i.e. gastrocnemius, biceps femoris) b Values taken from Johnson et al. (1973) and Edgerton et al. (1975). Data unavailable for extensor hallucis longus (value for tibialis anterior alone used in comparison to anterior tibial muscles) or peroneals c

Values at baseline (BR1)

with the anti-gravity muscles showing significant atrophy (k = -0.00260[0.00036], t = -7.1, p \ 0.0001) but the remaining muscles showing no atrophy (k = -0.00061 [0.00040]; t = -1.54, p = 0.12). Anatomical-type was less important (F = 4.5, p = 0.035) with both mono- and bi-articular muscles showing similar rates of atrophy (difference in rate of atrophy between mono- and bi-articular muscles: t = 0.1, p = 0.93) and there was no interaction between anatomical- and functional-type (F = .15, p = 0.70). Rates of muscle atrophy also showed a significant negative correlation with the proportion of muscle spindles distributed throughout a muscle (Table 4), indicating that muscles with a higher proportion of muscle spindles showed slower rates of atrophy. No significant correlation existed between rates of volume change and baseline muscle volume or type I muscle fibre percentage.

Discussion This study had a number of interesting and novel findings. First, it is to our knowledge the first study to show different rates of atrophy in the lower-limb muscles during prolonged bed-rest. This manifested itself in the greatest rates of atrophy in the plantarflexor muscles (medial gastrocnemius, soleus), followed by the monoarticular knee extensors (vastii), and then by the hip extensors/adductors (semimembranosus, semitendinosus, biceps femoris long head and adductor magnus). Muscles of the foot and ankle, such as tibialis posterior and the peroneal muscles were also quite strongly affected. The dorsiflexors (anterior tibial muscles), the toe flexors (flexor digitorum longus), the biarticular knee extensor and hip flexor rectus femoris, other anteromedial hip muscles (adductor longus, sartorius and gracilis) and short head of biceps femoris were comparatively less affected by prolonged bed-rest.

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Another intriguing finding was that there were significantly different rates of atrophy in synergistic muscles. The three heads of triceps surae all showed differing rates of atrophy, with that of the medial gastrocnemius being (statistically) greater than those of the soleus and lateral gastrocnemius. Atrophy of the adductor magnus muscle also occurred faster than that of its synergist, adductor longus. In the hamstring muscles, the semimembranosus, semitendinosus and biceps femoris long head all showed greater rates of atrophy than the short head of biceps femoris. Furthermore, of the knee extensors, the rate of atrophy of the vastii was much greater than that of the rectus femoris, which demonstrated no atrophy during bedrest. The findings of differential muscle atrophy occurring between individual muscle groups can be understood in light of the biomechanics of human bipedalism and the functional anatomy of the different muscles. Humans are obligate bipeds; implying that upright posture during stance, walking and other activities is maintained by the lower-limbs (Lovejoy 2005). This necessitates the generation of extension forces at the ankle, knee and hips joints, with greater (muscular) moments lower in the kinetic chain (e.g. ankle) needed to support the load above. With the removal of normal physical activity (e.g. bed-rest), it follows that the plantarflexors of the ankle are most affected, followed by the extensors of the knee and then those of the hip (as seen in the current study). The tibialis posterior and peroneal muscles are important not only in controlling leg movement during locomotion (Hunt et al. 2001), but also for supporting the medial longitudinal arch (Johnson and Christensen 1999; Kaye and Jahss 1991; Kulig et al. 2004), which itself is a uniquely human structure (Langdon 2005). Atrophy of the muscles controlling the medial longitudinal arch could potentially lead to problems of excessive foot pronation during walking after inactivity. This functional explanation of rates of muscle atrophy is supported by the finding of faster atrophy in the anti-gravity musculature. The patterns of differential rates of atrophy amongst synergists can also be understood in a similar light. Studies of muscle damage during exercise have shown that the vastii contribute more to repeated sitting-to-standing manoeuvres than the rectus femoris (Takahashi et al. 1994). Similarly, in combined hip and knee extension exercises (i.e. closed-chain exercises), the vastii are strongly recruited, whereas the rectus femoris is not (Enocson et al. 2005; Richardson et al. 1998; Tesch 1999). These combined hip–knee–ankle extension moments are required for moving the body into upright posture against gravity and in propulsion of the lower quadrant during locomotion. Adductor magnus also plays an important role

Eur J Appl Physiol (2009) 107:489–499

in extension of the hip and/or eccentric control of hip flexion (Montgomery et al. 1994) and is similarly recruited over adductor longus during combined hip and knee extension (i.e. closed chain exercises) (Enocson et al. 2005; Richardson et al. 1998; Tesch 1999). The short head of biceps femoris is considered to play a role solely in knee flexion, whereas the other members of the hamstrings group are also involved in hip extension moments (Montgomery et al. 1994). With inactivity and ‘‘unloading’’ of the lower-limbs, the more predominant roles that muscles, such as the vastii, adductor magnus and medial hamstrings play in the ‘‘extension tasks’’ of upright posture and in locomotion are no longer needed and therefore, in our opinion, show more rapid atrophy during bed-rest. The finding of more rapid atrophy of the medial gastrocnemius than the soleus is somewhat more puzzling. In humans, the soleus muscle has a higher percentage of slow (type I) muscle fibres than the two heads of gastrocnemius (Edgerton et al. 1975; Johnson et al. 1973). Typically, in bed-rest and spaceflight, lower-limb muscles with greater amounts of type I muscle fibre (e.g. soleus as opposed to medial gastrocnemius) are thought to show greater degrees of atrophy (Fitts et al. 2000), which would be in contrast to the current findings. Other studies in bed-rest and spaceflight have shown greater (Akima et al. 2007; Le Blanc et al. 2000; Shackelford et al. 2004), similar (Akima et al. 2001), and less (Berry et al. 1993) atrophy of the gastrocnemius muscles than the soleus, though unlike our work, these prior studies did not perform any statistical tests on these relative differences of atrophy. Resolving this issue would require pooling of data from a larger number of studies/subjects. Clearly, however, the triceps surae are strongly affected during inactivity and management of the bed-ridden patient must include exercises to maintain this musculature for control of stance and locomotion upon reambulation. The findings of the current study are also largely consistent with those of prior work. Berg et al. (2007) also noted a hierarchy of greater atrophy in the extensors of the calf, thigh and then hip musculature. Examination of data from other authors (Akima et al. 2001, 2007; Alkner and Tesch 2004b) suggests that they too have found a much greater effect of inactivity on the vastii as compared to rectus femoris, though these authors did not perform direct statistical tests comparing the muscles. Two other works (Akima et al. 2001, 2007) have also noted a similar pattern in the hamstrings of the least atrophy in the short head of biceps femoris, followed by biceps femoris long head, semitendinosus with the greatest in semimembranosus. The only other study separating the adductors muscles during analysis (Akima et al. 2007) found the relative atrophy of the adductor longus during 20-days of bed-rest to be almost double that of adductor magnus, which is in contrast to the

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current work. Also, we did not note any significant changes in muscle volume of the sartorius and gracilis muscles, which is consistent with one work by Akima et al. (2001) but not another (Akima et al. 2007). One of the difficulties of bed-rest studies are their immense cost and complexity which limits the number of subjects who can be included in each study. This can be problematic when findings are nonsignificant. This is, however, an argument for pooling data from a number of bed-rest studies to better assess the effects of inactivity on the musculature and other body systems. Interestingly, the correlation analyses showed that the rates of atrophy of individual muscles were largely unrelated to their size (and hence mass) at the beginning of the study. This would imply that other functional, neuromuscular or histological characteristics are more important in determining the rate at which individual muscles atrophy. In an attempt to answer this question we drew data from normative studies on muscle fibre type (Johnson et al. 1973; Edgerton et al. 1975) and muscle spindle distribution (Voss 1971). Whilst rates of atrophy appeared unrelated to the proportion of type I muscle fibres, those muscles with a higher proportion of muscle spindles exhibited slower rates of atrophy. These latter results must be treated with some caution, however, as the data from the subjects involved in the current study are not available nor data on different types of muscle spindle, which may differ between different muscles. Also, data on a sufficient number of muscles for other variables (e.g. fascicle length, pennation angle) were not available. The results of the study, however, do support an explanation of rates of muscle atrophy in relation to the functional characteristics of the muscles in daily activity, though further work is required to examine this issue. One issue that should be remembered when evaluating muscle atrophy during bed-rest is that shifts of body fluids can occur in acute supine lying and that these can influence muscle size (Conley et al. 1996). These fluid shifts are generally complete within 2-h (Conley et al. 1996) and in the current work, all scanning was conducted during bedrest and baseline scanning was conducted at least 10-h after the beginning of the bed-rest phase. Despite this, subjects lose approximately 700 g of body fluid in the first 2 days of bed-rest (Armbrecht, Belavy´, Felsenberg, unpublished observations; see also Belin de Chantemele et al. 2004), which is likely to influence muscle volume. Due to fluid loss, the rates of muscle volume loss reported here cannot be considered to precisely model the actual rates of muscle (fibre) atrophy. This is not a limitation on the results of the current study per se, as we were primarily interested in comparing rates of atrophy between muscles, and all muscles of the lower-limb would be similarly affected by a general loss of body-fluid.

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This study also has some important implications for patient management. The importance of differential muscle atrophy occurring both between individual muscle groups as well as between individual muscle synergists, is that it would result in muscle imbalances developing around the joints, which would likely result in altered joint biomechanics and hence increased joint wear and tear, pain and injuries, on return to full loading conditions. In terms of exercise prescription: first, the anti-gravity extensor muscles of the lower-limb are primarily affected and exercise design should best involve ankle plantar flexion and knee and hip extension activities. These tasks should not be performed in isolation, however, as, for example, isolated knee extension exercises appear to preferentially load the rectus femoris muscle (Enocson et al. 2005; Prior et al. 2001; Richardson et al. 1998; Tesch 1999). Rather, combined actions of hip and knee extension with ankle plantar flexion should be conducted. Such ‘‘closed-chain’’ resistance exercises, will preferentially load muscles, such as the vastii (over the rectus femoris) and adductor magnus (over adductor longus; Enocson et al. 2005; Richardson et al. 1998; Tesch 1999; Yamashita 1988). Finally, specific exercises for the plantar flexors should be considered as part of any post-disuse rehabilitation programme as these muscles are the most affected amongst the lower-limb muscles by inactivity (see also Price et al. 2003). In conclusion, the current study has found that the rates of atrophy differ between the muscles of the lower-limb, with the greatest rates of atrophy seen in the ankle plantarflexors, followed by the single joint knee extensors and hip extensors. Differential rates of atrophy are also seen between synergistic muscles, such as between the medial gastrocnemius, soleus and lateral gastrocnemius muscles and adductor magnus and adductor longus. These results demonstrate that muscle imbalances develop during extended periods of inactivity, potentially increasing the risk of injury on return to full gravity conditions. Thus, such deconditioned patients should be prescribed ‘‘closed-chain’’ resistance exercise, which targets the lower-limb antigravity extensor muscles which are most affected in bed-rest. Acknowledgments We thank the subjects who participated in the study, the staff of ward 18A at the Charite´ Campus Benjamin Franklin Hospital, Berlin, Germany and Boris Calakic, Petra Helbig, Christian Kainz and Gerhard Wolynski of the MR scanning centre for their 2-year involvement. Michael Giehl is thanked for assistance with the MR database. The Berlin Bed-Rest Study was supported by grant 14431/02/NL/SH2 from the European Space Agency. The Berlin Bed-Rest Study was also sponsored by the Charite´ Campus Benjamin Franklin, DLR (German Aerospace Center), Novotec Medical, MSD Sharp & Dohme, Lilly Germany, Servier Germany, HoffmannLaRoche, Siemens, Novartis and Seca. Daniel L. Belavy´ was supported by a post-doctoral fellowship from the Alexander von Humboldt Foundation. Tanja Miokovic was supported by grant number 50WB0720 from German Aerospace Center.

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Differential atrophy of the lower-limb musculature ... - Springer Link

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