Physiological and molecular mechanisms underlying the adaptation to physical inactivity

Question 1

Is physical inactivity just the opposite of physical activity?

Answer 1

Muscle disuse due to
	Sedentary behaviour
	Injury
	Serious illness/disability
	Low gravity
	Ageing

Question 2

Local vs whole body disuse?

Answer 2

o Muscle loss during 7 days bed-rest
 - 1.4 ± 0.2 kg
 - 3.1 ± 1.0 %
o Disuse and other tissues
 Disuse leads to a decline in bone mineral content
 Disuse does not seem to alter tendon cross sectional area, but does affect tendon function.
o Muscle disuse atrophy
 Decreased: functional strength, metabolic rate, bone mineral density, oxidative capacity, tendon function
 Increased: fat mass, insulin resistance

Question 3

What factors affect the rate of muscle disuse atrophy? (Duration of disuse)

Answer 3

Despite a ‘slow’ decline in muscle protein synthesis, muscle loss is more rapid earlier on into disuse

Question 4

What factors affect the rate of muscle disuse atrophy? (Muscle group)

Answer 4

 Muscle groups of the legs and back are more susceptible to disuse atrophy (LeBlanc et al., 1992).
 Postural muscles of the leg are the most susceptible to disuse atrophy (Akima et al., 1997)

Question 5

What factors affect the rate of muscle disuse atrophy? (Illness related complications)

Answer 5

 Under control condition, around 500g of muscle loss in first month
 Under cortisol condition, around 1500g of muscle loss in first month

Question 6

What factors affect the rate of muscle disuse atrophy? (Age)

Answer 6

 Kortebein et al., 2007 reported a ~950 g loss of leg lean mass in elderly individuals in 10 days of bed-rest.
 Paddon-Jones et al., 2004 reported a ~350 g loss of leg lean mass in young individuals in 28 days of bed-rest.

Question 7

What factors affect the rate of muscle disuse atrophy? (Muscle mass/training status)

Answer 7

After 21 days
• Trained: - 10%
• Untrained: - 11%

Question 8

What factors affect the rate of muscle disuse atrophy? (Gender)

Answer 8

After 21 days
• Men: - 11%
• Women: - 1.5%

Question 9

How does physical inactivity tip the balance? A tale of mouse and men? Remember the key role of nutrition in maintaining muscle protein balance?

Answer 9

o Early animal studies demonstrated that a decline in muscle protein synthesis occurred with disuse, though this was insufficient to explain the magnitude of muscle loss.
o Animal work went on to demonstrate that a rise in muscle protein breakdown also contributed to muscle disuse atrophy.
o Human work confirmed that basal muscle protein synthesis rates were impaired with disuse.
o Human work went on to demonstrate that an ‘anabolic resistance’ to nutrition also represents a key mechanism underlying muscle disuse atrophy. Moreover, that these impairments in muscle protein synthesis with disuse occur in the myofibrillar proteins and begin only a few days into disuse.
o No human data have confirmed a substantive quantitative role for muscle protein breakdown in sustained muscle disuse atrophy. However, indirect evidence supports an early rise in muscle protein breakdown, likely facilitating the initiation of atrophy and explaining the rapid loss of tissue in this early stage.

Question 10

What impacts the integrated physiology of protein synthesis most?

Answer 10

o Digestion/absorption? NO
o Post-prandial hormone response/microvascular perfusion? NO
o Skeletal muscle amino acid uptake? NO
o Intracellular signalling defects? YES

Question 11

What about the mechanisms inducing muscle protein breakdown?

Answer 11

We know the ubiquitin proteosome system is involved, and mediated via the atrogenes (MAFBx and MuRF1) – but what could regulate this pathway?

Question 12

Myostatin and disuse?

Answer 12

Cell line and animal work have suggested that myostatin can:
 inhibit mTOR signalling.
 initiate ubiquitin mediated muscle protein breakdown
 impair myogenesis by inhibiting the activation and proliferation of satellite cells

Question 13

One Week of Bed Rest Leads to Substantial Muscle Atrophy and Induces Whole-Body Insulin Resistance in the Absence of Skeletal Muscle Lipid Accumulation (Dirks et al., 2016)

Answer 13

In conclusion, 1 week of bed rest substantially reduces skeletal muscle mass and lowers whole-body insulin sensitivity, without affecting mechanisms implicated in high-fat diet–induced insulin resistance.

Question 14

CrossTalk proposal: The dominant mechanism causing disuse muscle atrophy is decreased protein synthesis

Answer 14

Whether reductions in MPS or accelerated rates of MPB in non-pathophysiological states of disuse drive human muscle atrophy is an important issue since the choice of a primary countermeasure to attenuate atrophy would rest on the mechanism that predominates. In this regard, based on examination of existing data from uncomplicated disuse atrophy in humans, it is our opinion that declines in MPS are the predominant mechanism, underpinning the decline in muscle CSA in non-diseased models of disuse human skeletal muscle atrophy. Thus, future work should focus on strategies to enhance the sensitivity of skeletal muscle in response to stimuli of MPS during disuse.

Question 15

CrossTalk opposing view: The dominant mechanism causing disuse muscle atrophy is proteolysis

Answer 15

It is clear that proteolysis plays an important role in disuse atrophy, perhaps the most important role. This conclusion is firmly rooted in modern interdisciplinary biology (Fig. 1A). It incorporates what we know about muscle cell signalling, gene expression at the mRNA and protein levels, protein biochemistry, proteasome and protease activities, and regulation of protein breakdown. Plus it is inclusive, applying equally to postural and respiratory muscles of rodents and humans.

Question 16

Skeletal muscle atrophy during short-term disuse: Implications for age-related sarcopenia

Answer 16

o Skeletal muscle disuse leads to rapid muscle loss and a multitude of negative health consequences.

o Short periods of muscle disuse (<10 days) are most prevalent and accumulate throughout the lifespan thus contributing to age-related muscle loss.

o Muscle loss during short-term disuse is poorly understood but may involve changes in both muscle protein breakdown and synthesis rates.

o Muscle disuse atrophy data in elderly and more compromised populations are lacking and so should form a major research focus.
o Understanding the mechanisms underlying short-term muscle disuse atrophy will allow the development of strategies for treating sarcopenia.

Question 17

Effects of aging on human skeletal muscle after immobilization and retraining

Answer 17

In conclusion, the present data shows that aging is accompanied by an attenuated rate of muscle atrophy in response to immobilization compared with that of young individuals, and importantly that old subjects demonstrate a diminished capacity to restore muscle size and muscle architecture during subsequent retraining. Moreover, immobilization led to reduced muscle activation in old but not young subjects. Thus the present data suggest that the adaptive plasticity in skeletal muscle mass and central nervous system function associated with unloading and subsequent remobilization, respectively, may differ between old and young individuals. Collectively, these findings suggest that old individuals may be more affected with respect to neural function, and young individuals more affected in terms of muscle size, in response to short-term immobilization. Furthermore, the present data indicate that aging is accompanied by an impaired ability to recover from disuse muscle atrophy, and, consequently, old individuals may need a longer time to recover from periods of disuse compared with young individuals.

Question 18

Two Weeks of Reduced Activity Decreases Leg Lean Mass and Induces “Anabolic Resistance” of Myofibrillar Protein Synthesis in Healthy Elderly

Answer 18

The present study demonstrates that 14 days of reduced steps in older adults induces small but measurable reductions in muscle mass that appear to be underpinned by reductions in postprandial MPS and are accompanied by impairments in insulin sensitivity and systemic inflammatory markers and postprandial MPS.