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Key Points

1) the same satellite cells that can repair muscle can be turned into fat cells within the muscle sheath given the right environment

2) the main factor in the creation of intramuscular adipose tissue is inactivity

3) intramuscular adipose tissue can decrease insulin sensitivity, increase inflammation, reduce recovery from training, and decrease strength

4) it can be reduced via diet and exercise

Adipose tissue functionality and distribution

Adipose tissue was originally thought to be inert tissue used as storage for excess calories and thus was only of importance to the body’s energy balance. This is not the case however, due to adipose tissue’s ability to secrete hormones and pro-inflammetory cytokines. Rather than being inert; adipose tissue influences a number of systems including the cardiovascular, musculoskeletal, metabolic and central nervous systems (Stehno-Bittel 2008, Fischer-Posovsky et al. 2007, Sepe et al. 2010).

There are several important types of adipose tissue located throughout the body, the location (Goodpaster et al. 2010, Gallagher et al. 2005) and type of adipose tissue (Wronska & Kmiec 2012) is a significant predictor of a number of conditions associated with obesity (Wronska & Kmiec 2012). Whilst some researchers have expressed that whole body adiposity is not as important as local adipose tissue when predicting disorders associated with adipose tissue (Addison et al 2014) it should be considered that whole body adipose will largely predict local adipose tissue.

There are two clearly distinguishable compartments of the adipose organ in the body, these are subcutaneous adipose tissue (SAT) and also visceral adipose tissue (VAT). More recently, increasingly sensitive technology such as magnetic resonance imaging (MRI) scanners have enabled the identification and measurement of other deposits of adipose tissue which contribute to whole body adiposity (Bernard et al. 1996, Thomas et al. 1998).

One such deposit of adipose tissue is intermuscular adipose tissue (IMAT), which previously has been referred to in the literature by a number of names including myostasis, intermuscular fat, intramuscular fat, as well as low density lean tissue. IMAT is considered to be the broadest definition when referring to the infiltration of the muscle by lipids (Addison et al. 2014) and for the purposes of this article “IMAT” is inclusive of adipose tissue accumulated between muscle groups, beneath the muscle fascia and intramuscular adipose tissue which is located within individual muscles (Vettor et al. 2009, Addison et al. 2014). This compartment of fat also includes most of the intramyocellular lipids (IMCLs) as well as the adipocytes present between muscle groups and between muscle fascicles (Vettor et al. 2009).

Causes of IMAT

The causes of IMAT are observed on a pathophysiological level as beginning with the stem cells, or satellite cells (SC) (Vettor et al. 2009).

The regeneration of muscle tissue is controlled largely by SCs, specifically a number of SCs committed to the task of muscle regeneration located adjacent to the plasma membrane of myofibers. These particular SCs are self-renewable (Fuchs & Segre 2000, Oreffo et al. 2005) and have the ability to differentiate into different types of cell (Asakura et al. 2007, Collins et al. 2005, De Coppi et al. 2006, Shefer et al. 2004).

In vivo SCs are typically in a dormant state (Hawke & Garry 2001, Schultz et al. 1978) however they can be activated by an increase in muscular work or muscular damage; for example prolonged exercise, or similarly they can be activated by myotrauma (Vettor et al. 2009). When activated SCs express myogenic transcription factors (such as Myf5, MyoD, MRF4) which in vivo promote muscle tissue formation (Tapscott et al. 1979). However SCs have been shown to be able to differentiate into adipocytes given a sufficiently adipogenic environment (Vettor et al. 2009).

Moreover, it has been shown by Shefer et al. 2004 during clonal analysis of SCs that Adult Mouse SCs could spontaneously differentiate into adipocytes, and that in the progeny from an individual clone myogenisis and adipogenesis were mutually exclusive. It is believed that the molecular cause of this shift from myogenic to adipogenic SC progenitors is due to an ectopic expression of peroxisome proliferator-activated receptors (PPAR), specifically PPARδ which in turn causes an upregulation of PPARγ (Vettor et al. 2009).

So what constitutes an Adipogenic Environment?

As previously mentioned, SCs will not differentiate into adipogenic cells without a change to the muscular environment. A number of conditions have been examined with regards to IMAT accumulation in vivo, spinal cord injury (SCI) was shown to increase thigh IMAT by an average of 26% on the three months following a complete SCI, which also accounted for a 70% reduction in glucose tolerance (Gorgey & Dudley 2007). The change to the muscular environment appears to be primarily down to inactivity, a number of causes have been identified for IMAT which are as follows; partial and complete SCI (Gorgey & Dudley 2007), whiplash associated disorder (Elliot et al. 2006), sporting injuries such as torn hamstring (Slider et al. 2008) and torn rotator cuff (Goutallier et al. 2003) as well as in the elderly and young-but-sedentary (Addison et al. 2014). All of these causes share a common characteristic which is an amount of time generally spent with limited mobility, partial local immobility or complete immobility, which was shown by Manini et al. (2007) to cause 15-20% increases in IMAT in the timespan of 30 days.

The effects of IMAT

Muscle structural composition is one of the most important factors which contributes to muscle function (Goodpaster et al. 2001). In older adults, muscle mass deterioration declines at a slower rate than strength, implying that factors other than decreased muscle mass contribute to the loss of strength (Kallman et al. 1990). A direct effect of IMAT on muscular strength has been shown in single limb experiments by Manini et al. (2007) and Tuttle et al. (2012) showed decreases in performance across a number of physical performance measures including a power test with increased IMAT. These decreases in strength, power and other physical performance measures are likely due to changes in the muscle form caused by IMAT. These changes in form include an increase of Muscle-Tendon unit stiffness caused by IMAT (Faria et al. 2009) which would cause decreased compliance, decreased elastic energy storage and more energy required to contract the muscle. In addition to this, research by Yoshida et al. (2012) has revealed a reduced activation in the quadriceps muscle group during a maximal isometric contraction. This reduction in activation of the muscle may be caused by a reduced ability for action potential to travel along the muscle sarcolemma, meaning the action potential will not reach certain areas of the muscle to stimulate calcium release and therefore muscle contraction.

Lean tissue (muscle) when viewed by a computed tomography (CT) scan in vivo can be divided into two distinct types; high density lean tissue where little fatty infiltration occurs and low density lean tissue where an elevated level of adipocytes can be found both between and within the muscle fibres which results in a decreased density when viewed on a CT scan (Addison et al. 2014). It has been stated that if the density of a muscle increases or if the area of low density muscle decreases post (exercise based) intervention, then the intervention has been successful in reducing both IMAT and IMCL.

Aside from the aforementioned physical changes to the muscle which are associated with IMAT, a number of metabolic changes take place within the muscle have been reported in individuals with IMAT. IMAT has been reported to reduce insulin sensitivity within the affected muscle (Goodpaster et al. 2000) although the exact mechanism for this interaction is unknown, it is assumed to be due to the proximity of the IMAT to the muscle (Beasley et al. 2009, Manini et al. 2007). There has also been a reduction in citrate synthase activity reported with increased IMAT levels (Jong-Yeon et al. 2000) which causes a reduction of Krebs cycle activity in the muscle. A third reported metabolic factor reported in conjunction with the aforementioned two aspects, is an increase in proinflammatory cytokines in high IMAT muscle (Beasley et al. 2009, Manini et al. 2007, Koster et al. 2011), the consequences of which are a reduction in muscular function (Schaap et al. 2006) and mobility ( Ferrucci et al. 2002)

There is increasing evidence that demonstrates IMAT’s role in reduced mobility in an aging population (Hilton et al. 2008, Marcus et al. 2012, Tuttle et al. 2011, Tuttle et al. 2012, Visser et al. 2005, Visser et al. 2002). Adults with significant IMAT levels have a decreased six minute walk distance (Marcus et al. 2012, Tuttle et al. 2012) potentially due to a reduced gait speed (Visser et al. 2002). There is also evidence in a reduced ability to perform ‘repeated chair stands’ (Visser et al. 2002) and stair descents (Marcus et al. 2012). With this in mind; IMAT is a strong indicator of future mobility impairment (Visser et al. 2005) but also of bone mineral density (Kim et al. 2012) which predicts an increase in hip fracture (Lang et al. 2010, Kim et al. 2012). This loss of mobility function associated with IMAT has been linked with the proinflammatory cytokines which are produced by the IMAT (Manini et al. 2007, Delmonico et al. 2009, Zoico et al 2010), which may be due to the fact that a number of authors have reported relationships between proinflammatory cytokines and reduced muscle and mobility function which are very similar to the relationships reported between IMAT and muscle and mobility function (Addison et al. 2014)

Reduction of IMAT

Exercise and a calorie restricted diet are often the first interventions most clinicians will prescribe in order for a patient with obesity and/or IMAT in order to achieve healthy weight loss and, in theory, reduction of IMAT accompanied by improved skeletal muscle function. Indeed a number of studies have reported a reduction in IMAT with intentional weight loss through calorie restriction or exercise (Ryan et al. 2012, Ryan et al. 2006, Goodpaster et al. 1999) and additionally, longitudinal twin studies have demonstrated that the inactive twin had significantly more IMAT than the active twin (Leskinen et al. 2009). Moreover, in SCI patients a high level of spasticity was found to protect against IMAT (Gorgey & Dudley 2008). The current consensus with regards to weight loss as a way of preventing or reversing IMAT is that IMAT is reduced following a nutritional or exercise based intervention (Prior et al. 2007, Durheim et al.2008, Ryan et al. 2000, Ryan et al. 2012, Christiansen et al. 2009, Marcus et al.2008, Murphy et al. 2009, Ryan et al. 2006, Taaffe et al.2009. Lee et al. 2005. Avila et al. 2010, Mazzali et al. 2006) and that exercise intervention has a significantly greater effect than nutritional intervention (Christiansen et al. 2009, Murphey et al. 2012, Mazzali et al. 2006). However, a recent study by Jacobs et al. (2014) showed no improvement in IMAT following a three month exercise intervention in elderly subjects. This difference in Jacob’s results compared to previous findings may be due to the population group examined, or perhaps the use of magnetic resonance imaging (MRI) to quantify IMAT levels as opposed to the CT scans used in many other studies.

IMAT appears to operate in a positive feedback loop, which is to say that dysfunction in the muscle leads to inactivity (or vice-versa) which then leads to increased levels of IMAT and further increasing insulin resistance and muscle dysfunction (Addison et al. 2014). This is supported by the notion that the changes in muscle performance and metabolism from IMAT may limit the degree to which the muscle responds to training stimulus (Marcus et al. 2013) and also the fact that SCs become adipocytes which limit the number of SCs dedicated to repairing muscle damage caused by training.

Editor’s Note: So you may be thinking, “What’s the takeaway here?” This is basically a cautionary tale against inactivity. Everyone knows that sitting on your tail all the time is bad for you – this is one specific way that inactivity can negatively affect your strength and health, and being active (not just “working out,” but living a generally active life) can benefit them. It should also be noted that not all intramuscular fat is bad. With training (specifically aerobic training), intramuscular adipose stores increase to provide the muscles with a supply of stored energy for activity (similar to muscle glycogen). However, this process is substantially different from the one outlined above for a few different reasons.

1) There’s not the same shift in stem cells toward adipocytes, compromising recovery. The bulk of IMAT stores resulting from training are in the form of lipid droplets within the muscle fibers themselves, not fat cells around the muscle fibers.

2) Accumulation of intramuscular adipose tissue resulting from training doesn’t decrease insulin sensitivity.

3) The accumulation of IMAT as a result of training is accompanied by increased number and size of mitochondria, increased levels of aerobic enzymes, and increases in the proteins necessary for the handling and transport of the lipids from the lipid droplets to the mitochondria.



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