MU is the fundamental functional unit in the neuromuscular
system, representing the final common pathway for the movement generation. The
MU, consisting of an alpha motor neuron housed in the spinal cord and the
muscle fibres it innervates, undergoes profound changes with aging. Indeed, age-related
loss of muscle mass originally results from a reduction in the total number of
MUs (Lexell et al., 1988). Early reports using electrophysiological
technique have estimated the MU numbers from various upper and lower limb
muscles and observed a more pronounced loss of MUs after the age of 60 years (Campbell et al., 1973; Brown et al., 1988; Doherty et al., 1993).
Consistent with this observation, recently McNeil and colleagues (2005)
estimated MU numbers in the tibialis anterior muscle among three distinct age
groups found that the loss of MU number using the groups of young (23-32 years)
men as reference was ~39% when compared with older (61-69 years), and a further
loss of ~61% in the very old (80-89 years) men. Notably, muscle mass did not
have such precipitous decline (i.e. ~35% from old to very old age for only a
further 15 years). Thus, it may support the notion that the loss of muscle mass
in normal aging process is secondary to the progressive loss of motor neuron (Aagaard et al., 2010; Hepple and Rice, 2016),
probably due to the maintenance of muscle fibres through the process of
‘successful’ collateral reinnervation in the early stages of MU loss (McNeil et al., 2005; McNeil et al., 2007).
The number of
motor neurons can be evaluated only via cadaveric studies. Tomlinson and Irving
(1977) provided a thorough examination of the number of limb motor neurons in
the lumbosacral cord in the healthy human throughout the lifespan (aged 13-95
years). Using histochemical staining procedures, they reported that there was an
approximately 25% average decrease in the number of motor neurons over the age
range from 20 to 90 years, with several specimens taken in old age (> 60 years)
demonstrating 50% fewer motor neurons compared with those specimens taken in
the age of 20-40 years (Tomlinson and Irving, 1977), thus suggesting that the loss
of motor neurons with aging is not a linear process. In addition, other observations
have demonstrated a decrease in both number (~5% per decade) and diameter of
motor axons in the ventral spinal roots (Kawamura et al., 1977; Mittal and Logmani, 1987),
with a more evident decrease in the large myelinated nerve fibre group (Mittal and Logmani, 1987), which per se could lead to a
slowing of motor nerve conduction velocity (Wang et al., 1999). The phenomenon of the selective loss of large
motor neurons can be, in part, attributed to MU remodelling, as initial
denervated fast-twitch muscle fibres are reinnervated by axonal sprouting from
adjacent slow-twitch MUs, so that the
same histochemical type muscle fibres from different MUs are likely to be
clustered within a specific area of the muscle (i.e. fibre-type grouping) (Lexell
and Downham, 1991). For older individuals,
therefore, each remaining MU consists of a greater number of muscle fibres, resulting
in a higher innervation ratio (Campbell et al., 1973; Fling et al., 2009).
Furthermore, it is important to note that the damaged motor axon withdraws from
the muscle fibres it innervates, but the denervated fibres are not all
successfully reinnervated; hence most denervated fibres will be lost eventually
(Hepple and Rice, 2016).
Advanced age is accompanied by a net reduction in the number
and size of individual muscle fibres, in particular in lower limb muscles, such
as VL and tibialis anterior muscles (Lexell et al., 1983; Lexell et al., 1988; Hunter et al., 1999).
These observations have been demonstrated
in aged muscle using either in
vivo by biopsy procedures or analysis of cadaveric samples (Larsson and Karlsson, 1978; Lexell et al., 1983; Lexell et al., 1988;
Klein et al., 2003).
The age-related muscle fibre atrophy occurs typically across all fibre types in vivo, with a preferential atrophy in
type II compared with type I muscle fibres, resulting in a greater whole muscle
type I:II fibre area in older
individuals (Lexell et al., 1988; Hunter et al., 1999; Purves-Smith et al., 2014).
Although not a universal finding, at least in part, age-related decrease in the
rate of myofibrillar protein synthesis and amount of satellite cells in type II fibres may contribute to the
age-related muscle fibre atrophy (Verdijk et al., 2007; Wall et al., 2015).
The atrophy of all types of muscle fibres with aging has
been confirmed by studies, in which both type I and type II fibres were reported to have
lower specific tension (i.e. Po/CSA)
in older compared with young individuals (Larsson et al., 1997; Frontera et al., 2000b).
For instance, Larsson et al., (1997) showed that the specific tension of
quadriceps muscle fibres was lower by 16%-25% for type I and 20%-28% for type II?
in older compared to young individuals.
older individuals, even for matched fibre type composition, when normalized to
muscle fibre CSA there is still an age-related reduction
in specific tension (D’Antona
et al., 2003). Different reasons have been
put forward to explain this reduction in specific tension with aging: (1) a
reduced myosin concentration, probably due to a diminution in the number of
cross-bridges (D’Antona et al., 2003);
(2) the decreased amount of endogenous and sarcoplasmic
reticulum (SR) Ca2+ content (Hunter et al., 1999); and (3) a reduced
Ca2+ sensitivity (Lamboley et al., 2015).
Muscle fibres of older individuals are not only weaker and
smaller, but also exhibit slower contractile properties compared with those of
young individuals. For instance, single fibres from quadriceps muscles have demonstrated
a lower maximal shortening velocity in elderly persons (Larsson et al., 1997; D’Antona et al., 2003).
The velocity of a single muscle fibre is determined by the different myosin
heavy chain (MHC) isoform expressions. It has been suggested that single muscle
fibres expressing MHC II?
isoforms are 3 × faster and 6 × more powerful compared to single fibres
expressing MHC I isoforms (Trappe et al., 2003).
Obviously, any shift towards MHC I
isoforms in old muscle would reduce its contractile velocity (Larsson et al., 1997; Trappe et al., 2003).
However, the changes in MHC isoform composition is not easily identified by
traditional classification which adopted the histochemical techniques based
on ATPase sensitivity to pH, expressing mainly MHC I, MHC II? and MHC IIx isoforms (Macaluso and De Vito, 2004). It has been
shown that muscle fibres are likely to co-express multiple MHC isoforms
in single fibre with aging, probably due to the age-related changes in the
amount of denervation and innervation within muscle fibres (Miller et al., 2013; Purves-Smith et al., 2014);
so caution is required in classifying fibres in older adults on the basis of
type I and type II categories
alone without considering the MHC isoform expression.
In line with the slowing of contractile properties, an age-associated
slowing of muscle relaxation has also been consistently observed in various
muscles of the lower limbs (Vandervoort and McComas, 1986; Connelly et al., 1999; Callahan and
The increased muscle relaxation time is probably linked to the slowing of the
myosin actin cross-bridge cycling and SR activity (Hunter et al., 1999; Miller et al., 2013).
For instance, in older women, the slower relaxation rate of the quadriceps muscles
assessed by electrical
stimulation was associated not only to a greater proportional area of
type I muscle fibres, but also to a lower maximal rate
of SR Ca2+ uptake and Ca2+-ATPase activity on biopsy
samples collected from the VL muscle (Hunter et al., 1999).
Overall, these findings suggest both structural and kinetic changes within the cross-bridge
cycling contributing to the age-related impairment in muscle performance.