Skeletal Muscle As A Pro and Anti Inflammatory Tissue: Insights From Children To Adults and Ultrasound Findings
Skeletal Muscle As A Pro and Anti Inflammatory Tissue: Insights From Children To Adults and Ultrasound Findings
https://doi.org/10.1007/s40477-024-00917-5
REVIEW PAPER
Received: 12 March 2024 / Accepted: 11 May 2024 / Published online: 21 June 2024
© The Author(s) 2024
Abstract
Previously regarded as a movement and posture control agent, the skeletal muscle is now recognized as an endocrine organ
that may affect systemic inflammation and metabolic health. The discovery of myokines such as IL-6, released from skeletal
muscle in response to physical exercise, is now one of the most recent insights. Myokines are the mediators of the balance
between the pro-inflammatory and anti-inflammatory responses. This underscores the muscle function as a determinant of
good health and prevention of diseases. Advances in ultrasound technology improved evaluation of muscle thickness, compo-
sition, and determining fat distribution. Combining imaging with molecular biology, researchers discovered the complicated
interplay between muscle function, cytokine production and general health effects.The production of myokines with exercise
showcasing the adaptability of muscles to high-stress conditions and contributing to metabolism and inflammation regula-
tion. These findings have significant implications in order to provide improvement in metabolic and inflammatory diseases.
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770 Journal of Ultrasound (2024) 27:769–779
biology have improved our understanding of the skeletal Adipokines and myokines in obesity: impact
muscle, no longer considered with the only role of a organ on metabolic health
of movement but also with a influencer of inflammation,
metabolic balance, and overall health [8]. In this paper we With the more advances of obesity research, the role of
explored literature from childhood to adulthood in order muscle and fat cytokines in systemic inflammation and the
to obtain a full picture of how skeletal muscle’s and fat related development of metabolic diseases have become
cytokines change over time in regulating metabolic and pro apparent [20]. With the more advances of obesity research,
and anti-inflammatory balance. An improving in understand- the role of muscle and fat cytokines in systemic inflamma-
ing this process, may provide an improvement in diagnostic tion and the related development of metabolic diseases have
and therapeutic assessment of health diseases related to an become apparent [21]. One of many adipokines, consist-
imbalance between muscle and fat cytokines production [9]. ency levels of TNF-α, IL-6, and IL-1β, are usually increased
among overweight individuals and they are related to insulin
resistance, a process in which adipokines cause change in the
Myokines way insulin is transmitted. However, the quoted cytokines,
one, can inhibit insulin receptor substrates and, two, acti-
Skeletal muscle tissue showed a pro- an anti-inflammatory vate serine kinase pathways, that result in the reduction of
role, with implication from childhood to adulthood [10]. insulin signaling [22]. Moreover, this increased production
IL-6 is a principal myokine secreted from skeletal muscles of pro-inflammatory cytokines leads to the transformation
during exercise and it is important for balancing inflam- of macrophages into adipose tissue, where they take part
matory and anti-inflammatory reactions [11]. In addition, in the inflammatory process [23]. Thus, a person who is
IL-6 increases insulin sensitivity and regulates the immune overweight or obese is more likely to have a deficit in anti-
response [12]. Skeletal muscle is also another producer inflammatory adipokines like adiponectin, and will, there-
of other significant myokines that include IL-8, IL-15, fore, have insulin resistance in higher levels that are also
and Fstl1 [1]. IL-8 is an angiogenesis promoting cytokine inversely related to the amount of fat stored in the body [24].
required for the formation of new vascular networks in While the reduction in adiponectin level is worrisome, due
muscle tissue and therefore muscle growth. One of IL-15 to its association with increased likelihood of metabolic syn-
main functions is to stimulate muscle growth as well as fat drome, cardiovascular disease, and type 2 diabetes, the rest
metabolism [13, 14]. The function of Fstl1 is to promote of the alterations are still to be studied [25]. On the other
tissue repair and regeneration [15]. Besides their specific hand, muscle tissue not only serves as a metabolic organ,
functions, the muscle myokines together enhance lipolysis but also a secretmem exerted in physical activity is raised
and endothelial function, vital for cardiovascular health [16]. in muscle tissue it additionally acts as an endocrine organ
The ultrasonography allowed monitoring of changes similar to a pancreas, producing myokines during physical
in muscle structure and function, thus revealing an exclu- activity. Acting in an array of autocrines, paracrines, and
sive view on the endocrine role of skeletal muscles [17]. endocrines have been demonstrated for these muscle-ori-
Ultrasound gives a good assessment of muscle thickness gin cytokines [1]. This group of myokines comprises IL-6,
and echostructure. Ultrasound also gives certain additional IL-15, and irisin proteins, which are secreted into the blood
indirect data concerning muscles state and metabolic activi- stream under muscle contractions. These proteins play an
ties associated with secretion of myokines [18]. Ultrasound active role in the metabolic homeostasis. For example, IL-6
is a detailed muscle thickness and structural change quan- that is released by muscle during the exercise and has lipo-
tifying tool, demonstrating how the skeletal muscle is a lytic and fatty acid oxidation effects [19]. An adipokine has
dynamic reactor to physical triggers with its endocrine role its negative side when released by an adipose tissue that
being underlined. The linkage of physical activity, myokine induces an inflammation, however in other situation body
secretion, and systemic health responses shows that muscles becomes anti-inflammatory when this adipokine is released
are crucial in metabolism maintenance and overall systemic by muscles during the mass [26]. IL-15 was linked to muscle
inflammation control [19]. Ultrasound studies findings, for growth and also the process of ‘browning’ of white fat where
example changes in muscle composition, and myokine secre- the white fat is converted into active brown fat through this
tion patterns, demonstrate not only exercise effect on the mechanism. This is an adipose tissue type that is more effi-
muscle but also its endocrine effect that is verifiable from cient in calorie burning [27]. Irisin; a myokine, a cleaved
childhood to adulthood (Fig. 1). membrane protein of FNDC5, has some proven to increase
the energy expenditure and thus might act as an important
anti-obesity and metabolic diseases factor [28].
Journal of Ultrasound (2024) 27:769–779 771
Fig. 1 Impact of muscle and fat mass on human health. The muscle growth, angiogenesis, energy storage, and tissue cell repair. Fat mass
tissue and fat tissues differ in their response to inflammation. Elevated accumulation cause adipokines release, leading to proinflammatory
myokines levels such as IL-6, IL-8, IL-15, and Fstl1 promote muscle state and increased insulin resistance
The balance between the adipokines, the myokines intri- control their over-production or blocking the receptors to
cately controls the general metabolism on the systemic level stop their damaging effect [31]. But the physical activity
thus setting a complex between calorie burning, inflamma- as the exercise has also other effects. It decreases the level
tion and metabolic-health rates. Conversely, the white adi- of adipose tissue, which is associated with proinflamma-
pose tissue produces the pro-inflammatory cytokines that tory states. Further to this, physical activity enhances the
cause toxinization of insulin receptor and result in higher positive effects of myokines. An example of this is that,
insulin resistance in muscles [29]. This is an indication that one should keep their muscles and be fit, always as this is
adipokines and myokines are both equal in modifying the very important to overall health [16].
metabolism. Yet, myokines, a product of exercise secretion, All things considered, the balance of the adipokine and
might control these counter effects through enhancement of the myokine is very important in the field of metabolic
insulin response sensitivity and genesis of anti-inflammatory homeostasis, especially in the course of obesity diseases
reactions [30]. [32]. There are lots of factors that push this balance, which
These pathways implicate and characterize the intri- include the diet, activity, and the genetic predisposition,
cate networks of cytokines that need to be determined and their disturbance leads to systemic inflammation and
in order to create potent management of obesity and its insulin resistance, which are the key features of obesity.
metabolic dysfunctions. Alternatives to therapeutic inter- The data indicates that inequalities are inbuilt and have
vention in this regard may involve targeting cytokines to always remained in the course of social life [33].
772 Journal of Ultrasound (2024) 27:769–779
ultrasonography and you should keep it as minimal as pos- individual, from birth to old age [57]. Ultrasonography is
sible to prevent it from having a negative effect on growth not only a crucial part of detection, but also of the moni-
and development [50]. The muscle ultrasound technique for toring process, as well as the story of how active muscle
evaluating the changes in muscle echogenicity and volume fibers work with their environment and coping with chronic
can provide an early detection of inflammatory myopathies inflammation while growing.
that would allow the clinicians to intervene in the disease
state and, as a result, an effective targeted treatment to alter
the course of the disease [49]. Ultrasound findings in obesity‑induced
While moving into adulthood the role of muscles changes muscle changes
from maturing to using them right and fighting inflammation
[51]. There ultrasonography rules as a measure of effective- The application of ultrasonography provides non-inva-
ness of muscle tissue rehab exercises. The underlying mech- sive information about skeletal muscle and adipose tissue
anisms of muscle-mediated anti-inflammatory effects can be throughout the lifespan (Table 1) [4]. These methods are
demonstrated through ultrasonography in a defined image based on the observation and classification of the progress of
[52]. This measurement is apparent while the muscle is in obesity-related changes in muscle and fat tissue in the body
motion as a result of physical activity. Ultrasound provides by utilizing a variety of scales and measurements. This sug-
as a mirror reflecting the tissue's reactions to exercise, where gests the interventions can be designed in a way which will
the improvements in muscle architecture and a decline in aim at various stages of life (Table 2) [58].
the level of inflammatory markers are demonstrated and as Contrast-enhanced ultrasound, a highly accurate very
a result it becomes obvious that physical activity preserves widely measuring technique, yields precise values of the
the organism against inflammation [52]. cross-sectional area (CSA) and thickness of important mus-
The golden years, as always, spawn their own issues, with cles in the leg, like the rectus femoris or gastrocnemius [59].
sarcopenia and gradual muscle mass and function loss being These are the techniques to compare the measured results
the leading ones [53]. Ultrasonography using a feature that with the normal data in the children’s age group to identify
provides with muscle mass and quality assessment becomes the abnormalities. An example is the Heckmatt scale, it was
an unreplaceable tool in detecting age-related pathology originally designed to evaluate muscle quality in patients
[54]. The ultrasonography method that includes the assess- with specific neuromuscular diseases [60]. It provides an
ment of body areas, such as muscle thickness, area of cross- assessment of muscle quality evaluating echogenicity from
section, and intramuscular fat concentration, provides a normal group to severe group and higher score indicates
comprehensive picture on the structural changes due to age more fat and connective tissues were infiltrated into the mus-
and helps to define the influence of age on muscle alterations cles [60].
[55]. Elastosonography can as well analyze muscle stiffness Indeed, the absence of differences from well-regulated
that may appears during fibrosis [56]. echo patterns and CSA measurements during this stage
In summary, from childhood to the elderly population, represents the loss of muscle strength due to obesity [61].
ultrasonography with the help of the utility of the technique In this stage the Doppler ultrasound technology is used to
provides a comprehensive depiction of the muscle health assess the perfusion and microvascularity of muscle [62]. A
[57]. It goes beyond classic imaging features and provides a Doppler ultrasound measures peak systolic velocity (PSV)
unique approach to observe how the inflammatory changes and end-diastolic velocity (EDV) and these values are an
in the muscles due to obesity lasts throughout the life of an indicator of the quality of the blood flow. Resistive indices,
Children Increased echogenicity Indicative of inflammatory myopathies and suggests the presence of fibrous [74, 75]
tissue and intramuscular fat, impacting muscle growth and metabolic health
Children Reduced muscle volume May indicate muscle atrophy or diminished muscle development due to [74, 75]
inflammation
Adults Increased echogenicity Correlates with intermuscular adipose infiltration and fibrosis, linked to [76, 77]
insulin resistance and decreased muscle function
Adults Changes in muscle architecture Visualized alterations can indicate ongoing inflammatory processes, poten- [76, 78]
tially affecting muscle strength and endurance
Children and adults Changes in muscles thickness Indirectly reflects muscle health, metabolic activity, and the secretion of [17, 18]
and echo intensity myokines within the muscle
Table 2 Ultrasound metrics: assessment of muscle and fat tissue
774
Scale Population Description Anatomical structures Normal range Variations from normal
Heckmatt Scale [60] Children Assesses muscle echogenicity Quadriceps, especially the rectus Grade 0 (normal) to Grade 1 Higher grades indicate increased fat
from normal to increased fibro- femoris, due to its accessibility (slight increase) and connective tissue, suggesting
sis and fat infiltration and size muscle pathology
Medial gastrocnemius, for its
propensity to show changes in
echogenicity due to its composi-
tion and function
Muscle Quality Index (MQI) [79] Adults Combines measurements of Biceps brachii and triceps brachii MQI < 25 (lower intramuscular Higher MQI scores may indicate
muscle size with the degree of in the upper extremities fat) sarcopenia or increased fat
intramuscular fat for an overall Rectus femoris and biceps femoris infiltration
assessment of muscle quality in the lower extremities, due to
their size and role in locomotion
Elastic modulus [77] Adults Quantifies muscle stiffness, Accessible and sizeable muscles < 8 kPa (indicative of normal tis- Increased values suggest greater tis-
often used in the assessment of such as the rectus femoris or sue stiffness) sue stiffness and potential fibrosis
fibrosis biceps brachii
These measurements are also use-
ful in deeper muscles, but acces-
sibility and the depth at which
reliable measurements can be
obtained may limit their use
Shear wave speed [77] Adults Measures the speed of shear Accessible and sizeable muscles 1–3 m/s (indicative of normal Higher values suggest increased
waves through muscle, related such as the rectus femoris or tissue elasticity) muscle stiffness and potential
to stiffness and used to assess biceps brachii pathology
fibrosis These measurements are also use-
ful in deeper muscles, but acces-
sibility and the depth at which
reliable measurements can be
obtained may limit their use
Peak systolic velocity (PSV) [80] All ages Assesses the maximum blood Measurements are often taken Generally ranges between 30 Lower values may indicate reduced
flow velocity in muscle during in the major arteries supplying to 100 cm/s, but this can vary muscle perfusion and potential
the contraction phase of the the muscle groups, such as the widely based on the artery's size pathology
heartbeat femoral artery for the lower and the patient's hemodynamic
limb muscles status
The brachial artery can be used
for upper limb muscle assess-
ments
Journal of Ultrasound (2024) 27:769–779
Journal of Ultrasound (2024) 27:769–779 775
hence, the values are very important for the state of tissue
Table 2 (continued)
first stages. Sarcopenia is defined by age-associated loss of The crosstalk between muscle mediated cytokines and
muscle mass and deterioration of muscles utilized in load- the systemic inflammation is critical for it places the skeletal
dependent activities. This assessment frequently includes the muscle as the main actor not only through movement but an
Muscle Quality Index (MQI), which considers muscle size active participant of metabolic well-being and of immunity
and simultaneously the amount and deposition of in Muscle responses regulation [42]. Systematic implementation of
[67]. Metabolic Quality Index (MQI) is a crucial parameter approaches designed for physiologic changes proposed for
that evaluates not only the condition of intramuscular fat but muscle in a way would make muscle tissue healthier, result-
also muscle area. The process of assessing intervention effi- ing in not only healthier metabolic profiles but also reduced
ciency in successful prevention or treatment of sarcopenia is chronic inflammation-associated diseases [73].
one of the most important tasks of the study [67].
In all the age groups auditioning subcutaneous and intrab-
Author contributions ADL wrote the manuscript and realized the fig-
dominal adiposity via ultrasound provides very key under- ure and table. SLB and FC (Francesca Ciarelli) wrote the manuscript.
standing of adiposity distribution, which physician refer to FC (Francesco Chiarelli), LB and AM coordinated, reviewed, and
as underlying body fat metabolism related diseases [64]. approved the final version of the manuscript. All authors have read and
Measuring subcutaneous fat (SAT) thickness at the standard- agreed to the published version of the manuscript. All authors take full
responsibility for the integrity and accuracy of all aspects of the work.
ised anatomical sites, such as the abdomen or thigh, enables
SAT distribution throughout the body estimation and pro- Funding Open access funding provided by Università degli Studi G.
vides an opportunity to reveal the association of metabolic D’Annunzio Chieti Pescara within the CRUI-CARE Agreement. This
risk factors with SAT accumulation [68]. manuscript received no external funding.
Through the physician’s interpretation, validation of Data availability Not applicable to this article as no datasets were gen-
index and scale, physical examination that is then confirmed erated or analyzed during the current study.
by ultrasonography, doctors can now identify, determine and
measure the pathological changes in the body tissues due to Declarations
muscle inflammation in obesity [69]. The analysis of differ-
Conflict of interest The authors declare that they have no competing
ent life stages allows us to comprehend the developing pat- interest.
tern as well as the effects of the obesity on skeletal muscles,
and the clinicians attain the age-specific tailored approaches Ethical approval All performed procedures were in accordance with
for personalised interventions in order to minimize the harm. the ethical standards of the institutional and/or national research com-
mittee and with the 1964 Helsinki Declaration and its later amendments
or comparable ethical standards.
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