What causes muscle loss?

Inactivity, atrophy, and muscle quality

As we get older, we're much more likely to be sedentary. Many researchers wonder whether we become sedentary before we lose muscle mass, or whether we become sedentary because we lose muscle mass 7 (Peterson and Gordon, 2011). It's hard to say for sure, but some researchers think muscle mass decreases because muscles lose their quality. By quality I mean ability to produce force. For example, muscles generate less force per unit of CSA with age (Mitchell et al., 2012; McGregor et al., 2014). More fat is deposited into muscle tissue possibly making muscles more inefficient (McGregor et al., 2014; Delmonico et al., 2009; Wagatsuma and Sakuma, 2014). Looking at molecular mechanisms, some studies suggest aging muscles develop problems with muscular contractions because of an impaired calcium release mechanism 8.

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7: it is seemingly logical to presume that sarcopenia precedes functional deficit and disability, but it also is likely that disuse itself may lead to exaggerated weakness and thus sarcopenia. (Peterson and Gordon, 2011) 8: A likely muscular contributor to dynapenia is impairment in the excitation–contraction coupling processes, which are series of biophysical events involved in converting the electrical signal for muscle activation into contractile force. Theoretically speaking, the disruption of any of the events in the excitation–contraction coupling process could result in the suboptimal activation of muscle, thus decreasing muscle quality (force per unit tissue area), and contribute to dynapenia. In particular, impairments in calcium (Ca2+) release from the sarcoplasmic reticulum have been suggested to explain the deficits of muscle quality (the intrinsic force-generating capacity of skeletal muscle relative to its tissue size) in aged muscle [113-123]. (Clark and Manini, 2012)

Anabolic resistance

Similarly to muscle quality, anabolic resistance is also a local mechanism. When we look at how the body responds to exercise, we see that it adapts by making our muscles more resistant to change. This has been studied in young lifters and it's called anabolic blunting (Coffey et al., 2005; Mangine et al., 2015; Gonzalez, 2015; Gonzalez et al., 2015a; Noguiera et al., 2015). In short, this blunting means that muscle protein synthesis and mTOR become harder to activate the more trained you get. In theory, this would partially explain why we experience diminishing returns as we grow bigger and stronger. So how does this link to aging? There’s now a debate whether anabolic resistance could happen to older people as well, even if they’re untrained. Some studies find that older lifters show anabolic resistance to strength training and nutrition (Kumar et al., 2009; Vingren et al., 2010; Horstman et al., 2012; Markofski et al., 2015; Moore et al., 2015; Wall et al., 2015; Moro et al., 2016; Timmons & Gallagher, 2016; Loenneke et al., 2016; McLeod et al., 2016; Mitchell et al., 2016; Shad et al., 2016). The theory is that the body slowly downregulates MPS and mTOR in a response to aging.

On the other hand, a new systematic review has just been published and it finds only partial support for the claim that MPS signalling becomes weaker with age (Shad et al., 2016). Shad et al. think a big reason there’s so much contradiction in the MPS literature is because of methodological differences between studies. A big limitation to Shad's review is that the majority of the studies they included only measured mixed muscle protein synthesis. This type of MPS does not predict hypertrophy. We need to look at myofibrillar protein synthesis (myoMPS) (Moore et al., 2009) if we want a shot at predicting gains (and in many cases, myoMPS does not predict gains either) (ASM). Here's an illustration of the differences between mixed MPS and myoMPS post-exercise: (illustration from Damas et al., 2015).

Ideally, Shad et al. would discard studies that measured mixed MPS and only analyze myoMPS. And since Shad isn't here right now I'll do it myself; out of the 24 studies included in Shad's review, 5 dealt with myoMPS. Three studies found a clear difference between young and old in terms of myoMPS responses (Babraj et al., 2005; Cuthbertson et al., 2005; Kumar et al. 2012), one study found differences at some time-points (Kumar et al. 2009), while one study found no difference (Atherton et al., 2016).

Here's an illustration of the differences, as per Kumar et al., 2009:

When we eliminate the mixed MPS studies, we see greater support for the anabolic resistance theory. There are also other studies outside of Shad et al's. review that support this (Welle et al., 1993; Welle et al., 1995; Yang et al., 2012). Several of these studies show that mixed MPS is actually quite similar between old and young, but myoMPS is blunted in the old 9 10.

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9: Whole body protein synthesis, assessed as the difference between leucine disappearance rate and leucine oxidation, was marginally slower (8%, P = 0.10) in the older group, but not when the data were adjusted for lean body mass. Myofibrillar protein synthesis was a smaller fraction of whole body protein synthesis in the older group (12 vs. 19%). Reduced myofibrillar protein synthesis may be an important mechanism of the muscle atrophy associated with aging. (Welle et al., 1993) 10: Posttraining myofibrillar synthesis was determined on the day after the final training session. There was not a significant change in fractional myofibrillar synthesis in either the young or the old group after training, and the rate in the older group remained 27% slower (P < 0.05). Whole body protein turnover increased approximately 10% only in the younger group, and 24-h urinary 3-methylhistidine excretion (an index of myofibrillar proteolysis) was not significantly affected by training. These data suggest that the slower myofibrillar synthesis rate in older subjects cannot be explained by disuse (Welle et al., 1995)

You might come across studies entitled "Aging does not impair the anabolic response to a protein-rich meal" (Symons et al., 2007), and they might seem convincing at first sight, but once you read conclusions like "Mixed-muscle FSR increased by approximately 51% in both [old and young]" you get disappointed at the researchers for not controlling for myofibrillar MPS.

From the information I've presented here, I think it's likely that MPS-related anabolic resistance exists. Beyond the studies that I've explicitly linked in this section, many of the studies and reviews I discuss in this article agree that MPS-related anabolic resistance is real. However, I will add the limitation that I have not systematically reviewed the literature, so it is possible that there are studies out there that contradict this hypothesis. In that sense, my conclusions are tentative, pending further evidence (as is everything in science...). Furthermore, do note that MPS correlates with gains only in some situations. In most situations researchers have looked at to date, it does not (ASM).

Declining anabolic hormones

Beyond mechanisms that affect the muscle tissue locally, the body experiences systemic changes with age. Most notably, systemic anabolic hormones like IGF-1, GH, and testosterone are reduced (Ryall et al., 2008; Vingren et al., 2010; Horstman et al., 2012; Tan et al., 2012; Fan et al., 2016; Budui et al., 2015). These reductions probably leads to muscle loss (Horstman et al., 2012; Mouser et al., 2016; Vitale et al., 2016). Testosterone drops by about 1-3% per year, beginning sometime during your thirties 11 12, GH and IGF-1 secretion declines by 14% per decade after the age of 30 13, and tissues become more insulin insensitive (Vitale et al., 2016)

Here's a relevant illustration by Ryall et al., 2008:

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11: Beginning around the age of 35–40 years, circulating testosterone concentration levels decrease by approximately 1%–3% per year (19) (Horstman et al., 2012) 12: Serum testosterone levels decline at a rate of about 1% per year from the age of 30–40 years in healthy men [7]. (Vitale et al., 2016) 13: Daily GH production has been reported to decline by 14% per decade after the age of 30 years, with a parallel decline in IGF-1 secretion [57]. This may represent an adaptive phenomenon to extend life span through the reduction of cancer risk. In fact GH and IGF-1 are both potent stimulators of cell proliferation [58]. On the other hand, this decline in GH/IGF-1 system contributes to several detrimental phenotypes of aging. (Vitale et al., 2016)

Inflammation

As we age, our bodies develop constant low-level inflammation (Jensen, 2008; Peterson and Gordon, 2011; Fan et al., 2016). Chronic inflammation likely affects muscle mass and strength negatively 14 15 16 17 18 19 20. There are several causes (Fan et al., 2016):



It gets even worse if you have diabetes, because this condition is characterized by inflammation (Park et al., 2009; Kalyani et al., 2014; Khor et al., 2014; Koster and Schaap, 2015; Jang, 2016; Vitale et al., 2016).

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14: in conjunction with chronic inflammation and oxidative stress, age-related apoptotic motor neuron loss is proposed to directly attenuate strength, rate of force development, and muscular power,10 and eventually lead to declines in muscle fiber number and physiological cross-sectional area. (Peterson and Gordon, 2011) 15: There is no simple mechanism to explain aging-associated loss of skeletal muscle. It is important to note that impaired cellular immune function combined with low-grade inflammation represents a continuous impact in aging process [7]. (...) aging is associated with prolonged inflammatory activity that is mainly attributed to progressively worsening muscle weakness (Fan et al., 2016) 16: It has been demonstrated that inflammation, along with oxidative stress, increase with aging both are considered significant contributors to age-related muscle wasting process (21, 22). Hence, some studies reported that high IL6 an C-Reactive Protein (CRP) levels are associated with increased risk of muscle mass and strength loss (23, 24). (Budui et al., 2015) 17: Inflammaging is the chronic low-grade inflammatory state present in the elderly, characterized by increased systemic concentrations of proinflammatory cytokines. It has been shown that inflammaging increases the risk of pathologic conditions and age-related diseases, and that it also has been associated with increased skeletal muscle wasting, strength loss, and functional impairments (Draganidis et al., 2016) 18: Sarcopenia is increasingly recognised as an inflammatory state driven by cytokines and oxidative stress [30]. (Robinson et al., 2012) 19: Changes of muscle constituent are another important cause of sarcopenia which is interrelated with other factors such as food intake, lifestyle, and chronic diseases including diabetes mellitus and cardiovascular diseases [34]. Other factors may include hormonal changes and the presence of proinflammatory cytokines [35, 36]. High level of proinflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor (TNF) has been reported to reduce muscle mass and strength [36]. (Khor et al., 2014) 20: the causes of sarcopenia are multi-factorial and can include disuse, changing endocrine function, chronic diseases, inflammation, insulin resistance, and nutritional deficiencies. (Wakabayashi and Sakuma, 2014)



Nervous system inefficiency and neural activation

The nervous system degenerates with age and it goes through multiple changes. Notably, the PNS loses muscle neurons (Frontera et al., 2011; Clark and Manini, 2012; Tintignac et al., 2015). These neurons are nerve cells that go from the spine to muscles and they control muscle contraction. Many authors now think this loss of neurons partially explain why muscles atrophy and we become weaker as we age (Kwan, 2013; McLeod et al., 2016) 21 22 23. However, others say that this might be the case, but we should wait for stronger evidence before we conclude anything for sure 24 (Manini et al., 2013). On the other hand, Manini's review is from 2013, and newer reviews think there is enough evidence to make conclusions (Sakuma et al., 2015). Beyond the physical decrease in motor neurons, the nervous system generally becomes more inefficient at sending messages. Manini et al. (2013) describe this as "neural noise" (i.e. static noise) which leads to "breakdown in communication between brain and muscle". Aging people could therefore have problems with voluntary neural activation and lowered maximal contraction 25.

From Clark and Manini, 2012: (Dynapenia = "Dynapenia is the age-associated loss of muscle strength that is not caused by neurologic or muscular diseases")

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21: Further examples [of muscle weakness] are age-related changes in the nervous system such as the loss of motor neurons, the remodeling of motor units through collateral re-innervation, and the impairment of neuromuscular activation manifested as a decreased maximal firing rate of motor units. (Frontera et al., 2011) 22: older adults possess fewer motor units compared with young adults [33,34]. Similarly, it is plausible that the muscle system’s ability to optimally produce force is impaired in dynapenic individuals, with this deficit in the intrinsic force-generating capacity of muscle (force/unit area) caused by potential changes in the excitation–contraction coupling process. (Clark and Manini, 2012) 23: As sarcopenic patients indeed show an increase in motor unit size (119), motor neuron loss may also contribute to the loss of muscle mass although reinnervation of muscle by the surviving motor neurons may delay this process. In addition to this presynaptic effect, there is plenty of evidence that changes in the function and the metabolism of skeletal muscle contribute to sarcopenia (Figure 7). Thus current evidence strongly indicates that sarcopenia is caused by pathological processes in both pre- and postsynaptic cells. (Tintignac et al., 2015) 24: Although age-related strength loss originates from multiple sources, the literature reviewed here suggests that a significant component is the breakdown in communication between brain and muscle. With aging, the changes in the central and peripheral nervous system may reduce an individual’s ability to activate available musculature. While there is a strong theoretical rationale for connecting brain and muscle, there is a general lack of evidence that shows brain aging is associated with muscle strength impairment in older adults. (Manini et al., 2013) 25: The impairments found in central activation are large enough to explain a large portion of observed muscle weakness in a given individual, such as inactivation on the level of ~ 15% or more [50,52,60]. One study that deserves particular attention is by Harridge et al. [50], which entails, to our knowledge, the oldest known cohort of individuals to date to undergo these types of assessments (n = 11, age range 85–97 y). In this study, all older adults required some degree of assistance with everyday activities, and—interestingly—all subjects showed evidence of incomplete voluntary activation during a maximal contraction, with activation ranging from 69% to 93% (mean 81 ± 7%). This finding suggests that deficits in voluntary activation can contribute to a significant portion of the muscle weakness observed in the very old. (...) Collectively, these findings suggest that aging results in decreased motor cortical excitability and cortical plasticity, which may contribute to age-related decreases in muscle performance. (Clark and Manini, 2012)

Genetics

Genetics is a huge and complicated subject so I will try to simplify as much as possible here. Researchers think people have different phenotypes. A phenotype is basically a collection of observable traits (physical features, mental abilities, etc.). Phenotypes are created from an organism's genes and their interaction with the environment. We now think that some phenotypes are at greater risk for sarcopenia because of heritability. It's estimated that muscle strength is 30-85% genetically inherited, while muscle mass is 45-90% inherited (Roth, 2012; Pereira et al., 2013), but the estimations vary depending on which review and study we look at (Tan et al., 2012). Update: a new systematic review and meta-analysis suggests strength is about 50% inherited (Zempo et al., 2016).

In addition to heritability, we have individual variation. Some individuals could lose a lot of muscle mass as they age, while others do not (Clark and Manini, 2012; Tan et al., 2012). This has been studied recently, and some older people that do strength training actually lose muscle mass. These people are referred to as non-responders, and it also happens in young subjects. You can see the non-responders at the bottom of this graph by Churchward-Venne et al., 2015:

There are some issues with measuring fat mass, LBM, water, etc. using DXA/BIA and similar methods. However, I won't go into that topic in this review.

We can also look at individual genes and analyse their relationship to muscle loss. The ACE, ACTN3, MSTN (myostatin), CNTF and VDR (vitamin D) genes are promising 26 (Khor et al., 2014). Some authors claim each of these genes can contribute 1-3% when it comes to skeletal muscle variation 27. It's possible that genes can also have synergistic effects. For example some genes could have a much stronger effect when combined 27. In that sense, no gene exists in isolation.

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26: The ACE, ACTN3, MSTN, CNTF and VDR genes have been associated with skeletal strength and/or mass in two or more studies. The MSTN gene was a strong contributor to variation in skeletal muscle phenotypes supported by the concordance of linkage studies, association studies and expression studies. (Tan et al., 2012). 27: Of those genes that have been identified, their importance to skeletal muscle-trait variation is generally small. None of the genes described above have been shown to conclusively contribute >5% of the inter-individual variation to their respective traits, and most are on the order of 1–3%. In addition to typical polymorphisms, copy number variation (multiple copies of the same gene), gene–gene interactions (multiple genes coordinated in a pathway), complex gene–environment interactions and epigenetic factors also contribute to the genetic component of inter-individual variability (Roth, 2012)



Low protein intakes

It's highly likely that sarcopenia is affected by low protein intakes (Shad et al., 2016). In fact, we need more protein the older we get (Moore et al., 2015; Philips, 2015; Shad et al., 2016; Mitchell et al., 2016; McLeod et al., 2016; Loenneke et al., 2016; Courtney-Martin et al., 2016; Baum et al., 2016). Adults that eat a lot of protein maintain ~40 % more muscle mass compared to those that eat very little protein 28.

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[themify_icon icon="fa-quote-left"] 28: data from the Health ABC study highlighted that older individuals in the highest quintile for protein intake (~19 % of total energy intake) lost ~40 % less lean mass than did those in the lowest quintile for protein intake (~11 % of total energy intake) (McLeod et al., 2016)

Micronutrient deficiency

Micronutrients are vitamins and minerals. It generally goes without saying that it's really important to get enough micros regardless of age. There are some micros that are particularly interesting; vitamin D. In general, low vitamin D levels could lead to muscle atrophy and reduced strength (Robinson et al., 2012; Roth, 2012; Wagatsuma and Sakuma, 2014; Khor et al., 2014; Wakabayashi and Sakuma, 2014; Budui et al., 2015). Nevertheless, there's a big BUT here: pretty much every review of the vitamin D literature agrees that results are inconclusive, so we can't say for sure how much vitamin D deficiency matters when it comes to strength and muscle mass.

Other causes

I don't have the time nor inclination to look at every single potential cause for sarcopenia in this article, but I will link you an illustration from (Miljkovic et al., 2015) that summarizes some potential causes: