Fiber Content and Myosin Heavy Chain Composition of Muscle Spindles in Aged Human Biceps Brachii
Department of Integrative Medical Biology, Section for Anatomy (J-XL,L-ET,FP-D), Department of Odontology, Clinical Oral Physiology (P-OE), Umeå University, Umeå, Sweden, and Center for Musculoskeletal Research, Gävle University, Gävle, Sweden (J-XL,P-OE,L-ET,FP-D)
Correspondence to: Fatima Pedrosa-Domellöf, Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, Sweden. E-mail: fatima.pedrosa-domellof{at}anatomy.umu.se
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Summary |
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Key Words: aging muscle spindles MyHC intrafusal fiber content biceps brachii human
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Introduction |
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Skeletal muscle fibers are characterized as fast or slow on the basis of their physiological, histochemical and biochemical properties, including their myosin heavy chain (MyHC) content. MyHC isoforms, key contractile muscle proteins, are the major determinants of the maximum shortening velocity in muscle cells, and a close relationship between the maximum shortening velocity and the MyHC composition has been documented in different species (Larsson and Moss 1993; Moss et al. 1995
; Bottinelli et al. 1996
; Schiaffino and Reggiani 1996
; Bottinelli and Reggiani 2000
; Pellegrino et al. 2003
). MyHCs are therefore considered the best markers of the functional properties of skeletal muscle fibers. The pattern of expression of MyHC isoforms is rather plastic and subject to a number of influences such as developmental cues, neural activity, and hormonal input as well as mechanical activity (for review see Pette and Staron 1997
, 2001
). Numerous studies have shown that human skeletal muscles undergo age-related changes in fiber type and MyHC composition (for review see Lexell 1995
; Monemi et al. 1999a
; Andersen 2003
; Thornell et al. 2003
). In human limb and trunk muscles there is an increase of type I fibers and slow MyHC isoform, concomitant with a decrease of type II fibers and fast MyHC isoforms during aging (Klitgaard et al. 1990
; Harridge et al. 1995
; Larsson et al. 1997
; Monemi et al. 1999a
). Furthermore, there is accumulating evidence showing that different muscles behave differently upon aging (for review see Thornell et al. 2003
). For instance, the age-related changes in the human masseter, a jaw-closing muscle, and the lateral pterygoid, a jaw-stabilizing muscle, are opposite to those reported for limb and trunk muscles (Monemi et al. 1998
; Monemi et al. 1999b
, c
). On the contrary, changes in the anterior and posterior bellies of the digastricus, a jaw-opening muscle, resemble those of limb and trunk muscles (Monemi et al. 1999c
; Monemi et al. 2000
).
Advanced age is also associated with significant changes in the physiological properties of the muscle spindle, the mechanoreceptor sensoring muscle tension and length. Muscle spindles have been considered to play an important role in voluntary and reflex movements (Miwa et al. 1995) and to contribute to position and velocity sense (Matthews 1981
). Both dynamic and static position sense deteriorate with advanced aging (Ferrell et al. 1992
; Meeuwsen et al. 1993
; Robbins et al. 1995
; Verschueren et al. 2002
) and movement detection thresholds appear to increase in the elderly (Skinner et al. 1984
; Gilsing et al. 1995
; Thelen et al. 1998
). A decrease in the dynamic sensitivity of muscle spindle primary endings has also been described in aged rats (Miwa et al. 1995
).
Morphological changes in the innervation and structure have also been reported in aged muscle spindles. Changes in the fine structure of the muscle spindle innervation consisting of spherical axonal swellings and expanded, abnormal motor end-plates have been described in some old muscles (Swash and Fox 1972). Additionally, an increase in the spindle capsular thickness and a decrease in the number of intrafusal fibers per spindle have also been observed in aging muscles (Swash and Fox 1972
).
Muscle spindles contain three types of intrafusal fibers: nuclear bag1, nuclear bag2 and nuclear chain fibers (Barker and Banks 1994). Each type of human intrafusal fiber contains a particular combination of MyHC isoforms (Thornell et al. 1988
; Thornell et al. 1989
; Pedrosa-Domellöf et al. 1993
; Eriksson et al. 1994
; Liu et al. 2002
; Liu et al. 2003
). We have previously shown very complex patterns of co-expression of several MyHC isoforms for each intrafusal fiber type in muscle spindles of biceps brachii from young human adults (Liu et al. 2002
). Both nuclear bag1 and bag2 fibers contained slow tonic MyHC (MyHCsto) along their entire fiber length and slow MyHC (MyHCI),
-cardiac MyHC (MyHC
-c), fetal MyHC (MyHCfet) and embryonic (MyHCemb) with regional variations. Nuclear chain fibers had a homogeneous content of MyHCfet and MyHCemb, and they contained fast MyHC (MyHCIIa) along a variable part of their length. However, no data have thus far been reported on the fiber type and MyHC composition of muscle spindles in the elderly. To investigate whether there are age-related changes in human muscle spindles with respect to intrafusal fiber types and MyHC composition, we examined muscle spindles of biceps brachii taken from subjects aged 69 to 83 years old. Our results show an altered fiber type composition and pattern of MyHC expression in the muscle spindles of the elderly.
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Materials and Methods |
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Enzyme Histochemical Classification of Fiber Types
The muscle spindles were analyzed in three regions: the A region, including equator and juxtaequatorial parts, containing the periaxial fluid space; the B region, extending from the end of the periaxial fluid space to the end of the capsule, and the C region corresponding to the extracapsular portion of the spindle (Barker and Banks 1994). Each region was further subdivided into an inner (proximal to the equator) and outer (distal to the equator) portion.
The intrafusal fibers were classified as nuclear bag1, bag2 and chain fibers according to their alkaline and acid mATPase activity (Ovalle and Smith 1972). In brief, fibers having low staining intensity at pH 4.3 and 10.4 in the outer A and B regions were classified as nuclear bag1 fibers whereas fibers showing high mATPase activity at pH 4.3 and moderate mATPase activity at pH 10.4 in the outer A and B regions were identified as nuclear bag2 fibers. The nuclear chain fibers could be recognized by their high mATPase activity at pH 10.4 and low activity at pH 4.3. In the C region, the distinction between bag1 and bag2 fibers could be carried out at pH 4.6. Fibers with very high mATPase activity were classified as bag2 fibers and those with moderate or low activity as bag1 fibers.
Analysis of MyHC Isoforms of Intrafusal Fibers
Monoclonal antibodies (MAbs) specific for various MyHC isoforms were used (Table 1). In addition, MAb NCL-MEROSIN against laminin 2 chain (Sewry et al. 1997
) was used to double label the contours of the muscle fibers in some sections. All antibodies were diluted in 0.01 M PBS containing 0.1% bovine serum albumin (BSA) and used at their optimal dilution (Liu et al. 2002
).
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The sections were examined using a Nikon microscope (Eclipse, E800; Tokyo, Japan) or a Zeiss microscope (Zeiss; Oberkochen, Germany). Computer-generated images were processed using the Adobe Photoshop software (Adobe System Inc.; Mountain View, CA).
Young Adult Subjects
To determine whether there was a difference in the number of intrafusal fibers between muscle spindles from old and young subjects, we used our previous data on muscle spindles from young adults (Liu et al. 2002). In brief, a total of 36 muscle spindles (25 from females, 11 from males) were examined in 12 muscle samples collected at autopsy from the biceps brachii muscle of four females (ages 48, 38, 19 and 15) and six males (ages 38, 37, 27, 25, 22 and 29).
Statistical Analysis
The null hypothesis that there was no difference in the number of intrafusal fibers between muscle spindles from old and young subjects was rejected at the 0.05 level of significance. Unpaired t-test and the StatView software (3rd edition, SAS Institute Inc., Cary, NC) were used for statistical analysis.
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Results |
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Fiber-type Composition
The intrafusal fiber-type composition was studied in 21 muscle spindles (16 from males, 5 from females) encountered in either the A or inner B region, where the full complement of intrafusal fibers is present. On average, there were 6.2 intrafusal fibers per spindle, including 1.8 (range from 1 to 3) bag1, 1.7 (0 to 5) bag2, and 2.8 (0 to 8) chain fibers (Table 2). Nineteen percent of the muscle spindles contained one bag1, one bag2, and two to four chain fibers. The remaining spindles contained three or more bag fibers except for one muscle spindle that contained only one bag1 and one chain fiber (Figure 7E). Of 21 muscle spindles, 16 had a unique allotment of numbers of nuclear bag1, bag2, and chain fibers (Table 2).
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Nuclear Chain Fibers
The nuclear chain fibers were unstained with anti-MyHCsto (Figure 4B), anti-MyHCI/1st, or anti-MyHCI/2nd (Figures 4C and 4D), whereas they were strongly and uniformly stained with anti-MyHC "all except IIx" (Figure 4G). In the B region, all chain fibers were stained strongly with anti-MyHCI+ IIa* and anti-MyHCIIa, whereas in the A region 10 and 12% of the nuclear chain fibers were unstained with anti-MyHCI+IIa* (Figure 4E) and anti-MyHCIIa (Figure 4F), respectively. These two antibodies stained the remaining chain fibers strongly to weakly in the A region (Figures 4E and 4F). The vast majority of the chain fibers were strongly or moderately stained with anti-MyHCfet (Figure 4H) and only a few chain fibers were unstained (1%) in the A region. Likewise, anti-MyHCemb stained all chain fibers strongly and evenly along their entire length (Figure 4I), except for three chain fibers that were transiently unstained in the A region. Nuclear chain fibers were unstained with anti-MyHC-c in the A or the inner B regions (Figures 7A and 7E). However, six chain fibers belonging to two muscle spindles showed weak staining in the A or inner B regions (Figure 7F).
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Discussion |
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Alterations in Intrafusal Fiber Composition
A decrease in the number of intrafusal fibers and increased capsule thickness with increasing age have previously been reported in human muscle spindles (Swash and Fox 1972). However, no data were available on the fiber-type composition of the old muscle spindles. In the current study we showed that the average number of both nuclear bag1 and bag2 fibers per spindle did not change with increasing age whereas the nuclear chain fibers decreased significantly in number or were completely absent in some muscle spindles. Our data also showed that the chain fibers became much shorter in the aged spindles as they were seldom seen in the inner B region and were not found in the outer B or C regions. The factors regulating the decline in the number of chain fibers remain to be determined. However, deefferentation in the neonatal period is known to influence intrafusal fiber number (Soukup et al. 1993
; Zelena and Soukup 1993
); therefore, changes in innervation are likely candidates influencing the number of chain fibers in the aged muscle spindles.
The functional significance of muscle spindles lacking or having fewer nuclear chain fibers remains to be elucidated. One would expect those muscle spindles to have a relatively less static sensitivity compared with the muscle spindles from young adults. This assumption is supported by previous physiological data that revealed a decline in static position sense at the ankle joint in the elderly (Meeuwsen et al. 1993; Robbins et al. 1995
). A deterioration in the dynamic position sense has also been observed with aging (Verschueren et al. 2002
), but it was 6-fold smaller than the deterioration observed in static position sense (Robbins et al. 1995
; Verschueren et al. 2002
). The question whether the diminution of the static sensitivity is related to the reduction in the number of nuclear chain fibers or whether it is due to alterations of the biomechanical properties of the aged muscle still remains to be determined.
Alterations in MyHC Composition
The present study showed that aging caused significant changes in the patterns of expression of MyHC-c, MyHCfet and MyHCI, although the typical profiles of MyHC composition of intrafusal fibers observed in old subjects were generally similar to those observed in young adults. Nuclear bag1 and bag2 fibers from aged muscle spindles were not as frequently and strongly stained with anti-MyHC
-c in the A region as those from young adults. Instead, they were mostly unstained or occasionally stained weakly to moderately, indicating a significant reduction in the MyHC
-c content in the aged nuclear bag1 and bag2 fibers. A similar reduction has also been observed in rat nuclear bag1 fibers after neonatal and adult deefferentation (Pedrosa et al. 1990
; Walro et al. 1997
; Wang et al. 1997
) and in both nuclear bag1 and bag2 fibers after a 14-day period of hypogravity (De-Doncker et al. 2002
). In contrast to the nuclear chain fibers in young adult biceps, some nuclear chain fibers in old muscle spindles showed novel expression of MyHC
-c isoform. Novel expression of MyHC
-c has also been observed over a short distance in the A region in nuclear chain fibers of rat soleus muscle after 14 days of hindlimb unloading (De-Doncker et al. 2002
).
The expression of MyHCfet was downregulated in nuclear bag2 fibers, and the presence of MyHCI extended into the B and A regions of nuclear bag1 fibers. The downregulation of the expression of MyHCfet in bag2 fibers and upregulation of MyHCI in bag1 fibers were also reported in nuclear bag fibers following deafferentation in adult rat muscle spindles (Walro et al. 1997; Wang et al. 1997
). It is possible that the parallel changes in MyHC composition found in the present study of aging spindles and those reported following deafferentation in adult rat spindles (Walro et al. 1997
; Wang et al. 1997
) might be caused by similar neural factors. However, the number of intrafusal fibers does not change following deafferentation in the rat (Walro et al. 1997
; Wang et al. 1997
), indicating that the changes seen with human aging are more complex and may be multifactorial. We suggest that deterioration in the motor and sensory innervation might cause the phenotypic changes observed in aged muscle spindles and are likely to have an impact in motor control in the elderly, as the muscle spindles play important roles in voluntary and reflex movements and, together with skin and joint sensory organs, also contribute to position and velocity sense.
In conclusion, the present study suggests an age-related loss of intrafusal fibers and changes in MyHC expression. Loss of fibers was found for the chain group and changes in MyHC expression for MyHC-c, MyHCI and MyHCfet isoforms. Notably, the results imply that aging does not affect all muscle spindles or each intrafusal fiber in the same way, further supporting the concept that each muscle spindle is particularly adapted to its functional context.
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Acknowledgments |
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We thank Drs A. Kelly, D.A. Fischman, J.J. Leger, and S. Schiaffino for kindly providing antibodies. We also thank Inga Johansson for excellent technical assistance.
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Footnotes |
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