Front Matter

Chapter 3 Musculoskeletal Structure and Physiology 55

loss (Pagano et  al., 2015). Concentric, but not
eccentric, exercise can retard sarcopenia.
Concentric activity includes weight training
and isometrics. Aquatic therapy, limb weight­
ing, and balance board exercises emphasize
concentric activity and might be useful compo­
nents of rehabilitation and fitness programs for
elderly sarcopenic animals.

Cytokines and skeletal muscle

Skeletal muscle is highly responsive to a wide
variety of cytokines, chemokines and growth
factors, and the prevailing milieu of biological
mediators controls many aspects of muscle
growth, repair, and adaptation. Infiltrating
leukocytes, particularly macrophages, are an
important source of many cytokines that
influence muscle homeostasis. Myofibers
produce a variety of cytokines, termed
myokines, that exert local autocrine and parac­
rine effects (Pedersen et al., 2007). The effects of
cytokines upon skeletal muscle homeostasis are
mediated by complex and highly integrated
intracellular signaling, transcriptional, and
translational processes within the myofiber.
These dynamic signaling systems are further
influenced by a wide range of mechanical
stimuli, pharmacological agents, and diet
(Sakamoto & Goodyear, 2002; Tisdale, 2007).
Exercise leads to enhanced skeletal muscle
myofibril deposition and hypertrophy
(Miyazaki & Esser, 2009; Gundersen, 2011). This
involves mechanoreceptor stimulation, but also
relies on increased insulin‐like growth factor
1  (IGF‐1) expression, decreased myostatin
synthesis, and enhanced satellite cell differen­
tiation. Exercise increases insulin‐independent
glucose transport and insulin sensitivity, which
in turn leads to myofibril protein synthesis
(Spangenburg, 2009). Exercise also stimulates
the production of myokines. The myokine
interleukin 15 (IL‐15) has received considerable
attention due to its ability to abrogate myofibril
proteolysis, maintaining the myofiber in a
hypertrophic state (Argiles et  al., 2009). IL‐15
also enhances skeletal muscle energetics
through stimulation of lipolysis in both muscle
and adipose tissue. The anabolic effects of IL‐15
on muscle and adipose tissue metabolism
suggest the activity of this cytokine may open
an interesting pharmacological avenue for

improving lean body mass (LBM), especially in

age‐related sarcopenia.

Interleukin 6 (IL‐6) appears to play an inter­

esting role in exercise as it is directly made by

skeletal muscle during exercise. There appear

to be strong correlations between plasma and

muscle IL‐6 concentrations and glycogen

depletion during prolonged exercise (Nieman

et  al., 2015). This increase in IL‐6 is currently

thought to be a systemic signal that allows for

hepatic upregulation of glucose synthesis as

part of a complex milieu of events that lead to

cross‐talk between skeletal muscle and hepatic

tissues to ensure homeostasis during exercise

(Knudsen et al., 2016).

Cytokines play a key role in the repair and

regeneration of muscle after injury. Following

acute traumatic injury such as strain or lacera­

tion, skeletal muscle has a strong capacity for

regeneration; however, this is dependent upon

the nature and duration of the post‐traumatic

inflammatory response as well as the mechan­

ical strains present at the site. The inflamma­

tory response that occurs following muscle

injury is biphasic (Tidball & Villalta, 2010). The

initial phase is an innate immune response

characterized by infiltration of damaged

muscle by neutrophils and proinflammatory

M1 macrophages that elaborate Th1 cytokines

such as tumor necrosis factor α (TNFα) and

interferon γ (IFNγ). Production of oxidants by

leukocytes during this phase leads to addi­

tional secondary muscle injury. During the

early inflammatory phase, local satellite cells

become activated and begin to proliferate.

Approximately 24 hours post‐injury, M1 mac­

rophages begin gradually to be replaced by a

second population of counter‐inflammatory

M2 macrophages, which downregulate the

acute inflammatory process through produc­

tion of cytokines such as IL‐4, IL‐10, and IL‐13.

Many mitogenic and differentiating signals

are produced during this later phase including

hepatocyte growth factor, insulin‐like growth

factor‐1 (IGF‐1), fibroblast growth factors and

vascular endothelial growth factor. These sig­

nals can stimulate the expression of myogenic

transcription factors within proliferating satel­

lite cells, marking the onset of myoblastic dif­

ferentiation (Ten Broek et al., 2010). Myostatin

is also upregulated during this phase, which

slows proliferation of satellite cells and