Amyotrophic lateral sclerosis as a disease model of sarcopenia

Abstract

Key Points

• Sarcopenia has traditionally been viewed as an age-related process.

• However, sarcopenia can occur earlier in life in association with various conditions including neuromuscular disorders.

• Amyotrophic lateral sclerosis and age-related sarcopenia share some common characteristics.

• New therapeutic agents targeting the skeletal muscle may be beneficial both in the amyotrophic lateral sclerosis (ALS) and in the age-related sarcopenia context

Sarcopenia, the progressive decline of muscle mass and function, has traditionally been viewed as an age-related process leading to a broad range of adverse outcomes, including falls, institutionalisation, loss of independence and mortality [1]. However, it has been widely reported that sarcopenia can occur earlier in life in association with various conditions (i.e. disease-related sarcopenia), including neuromuscular disorders, end stage liver and kidney diseases, type 2 diabetes and cancer [1, 2]. In this context, amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the human motor neurons in the brain and spinal cord system with a typical onset in the middle-to-late 50s, but it can manifest up to 80 years of age [3, 4]. Although ALS is considered a rare disease, the number of patients with ALS is steadily increasing as a result of population ageing [5]. The disease progressively impairs upper and lower motoneurons, leading to muscle spasticity, atrophy, and early death [3]. Mean survival of ALS patients is usually between 3 and 5 years after disease onset, with respiratory failure being the primary cause of death as the disease progresses [5]. Most ALS cases are sporadic, while a small percentage are familial [5].

As early as 2010, the European Working Group on Sarcopenia in Older People (EWGSOP) included neurodegenerative diseases characterised by motor neuron loss among the mechanisms underlying sarcopenia (Figure 1) [2].

Figure 1

Main mechanisms of sarcopenia. Adapted from Cruz-Jentoft et al. [2] under the Creative Commons CC-BY-NC licence which permits non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.

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Despite some differences in pathogenetic mechanisms, both ALS and age-related sarcopenia share common characteristics, such as the loss of motor units and muscle fibre atrophy [6], oxidative stress, mitochondrial dysfunction and inflammation [7]. The histology of the older muscle shows fibre size heterogeneity, fibre grouping and a loss of satellite cells, similar to what is observed in ALS patients [8]. Regrettably, the sarcopenic process in ALS patients has been largely overlooked, and literature on the condition in this patient group is very scarce.

Age-related sarcopenia is a symmetrical, generalised and slow progressive process. In contrast, in ALS patients, the sarcopenic process is asymmetrical, distal, fast progressive and generalised, with a particular involvement of respiratory muscles [4]. It is widely recognised that age-related sarcopenia is not limited to lower limbs but can affect muscles involved in breathing and swallowing, characterising the so-called ‘sarcopenic dysphagia’ condition [9]. Dysphagia is also a prominent condition in ALS patients. However, the consensus diagnostic criteria for sarcopenic dysphagia suggest that reduced muscle mass and strength, as well as dysphagia due to neuromuscular diseases, should not be included in the definition of dysphagia caused by sarcopenia [9]. This is likely to exclude secondary causes of the condition in older people. Notwithstanding, the early detection of both conditions (i.e. sarcopenia and dysphagia) and prompt interventions should be offered to both ALS patients and older people. Various screening assessment tools to early identify the risk of dysphagia and sarcopenia in older people could be also applied to ALS patients. To date, the Eating Assessment Tool (EAT)-10, a 10-item screening method to early identify individuals at risk for dysphagia, was developed and validated for various patient groups, including ALS patients [10]. The SARC-F, a simple questionnaire composed of five items (i.e. Strength, Assistance with walking, Rising from a chair, Climbing stairs and Falls) [11], has been recommended by the EWGSOP as the first step for sarcopenia risk screening [1]. The SARC-F questionnaire could also be easily implemented in the routine evaluation of ALS patients to screen for sarcopenia, as reported by some studies [4, 12]. Regarding muscle function, traditional measures of muscle strength used in the age-related sarcopenia context, such as handgrip strength or the chair stand test, may also be applicable to ALS patients, depending on the predominant involvement of lower extremities versus upper limbs function and vice versa. Muscle mass can be evaluated through dual energy X-ray absorptiometry (DXA) and bio-impedance analysis (BIA). However, DXA measures are often not feasible due to their lack of portability and of availability in most settings. On the other hand, BIA is considered a more affordable, widely available and portable tool [1], and its use has been validated in ALS patients [13]. Measures of physical performance like gait speed, the short physical performance battery, the timed-up and go and the 400-m walk tests may be used, in line with the EWGSOP2 algorithm, as a subsequent step in ALS patients to assess mobility function and the severity of sarcopenia. However, it is evident that those ALS patients with a completely compromised mobility function will fall into the severe sarcopenia category.

Unfortunately, at this time, there is no approved specific pharmacological treatment to reverse damage to motor neurons or cure ALS [14], just as there is none for sarcopenia [15]. There are only two approved drugs, riluzole and edaravone, for slowing the progression of ALS. Recently, the antisense oligonucleotide tofersen was approved by the U.S. Food and Drg Administration and European Medicine Agency for the treatment of only ALS patients carrying the superoxide dismutase 1 gene mutation. Interestingly, some agents targeting the muscle, like myostatin and mammalian target of rapamycin inhibitors, are under investigation both in the sarcopenia [15] and ALS context [14]. Given that poor nutritional status is a prognostic factor in ALS, it is thus crucial to provide proper nutritional support to ALS patients [12, 13]. Nutritional strategies include an adequate calorie and protein diet, dietary texture modification based on masticatory and swallowing function and placement of a feeding tube based on disease status [7]. Rehabilitative strategies integrating exercises for muscles dedicated to breathing and swallowing are also pivotal.

In conclusion, ALS can be clearly envisioned as an accelerated disease model of sarcopenia. The skeletal muscle, being one of the most affected by motor neuron degeneration, is emerging as a potential target of intervention in ALS. The early identification of poor prognostic factors like muscle decline might influence disease progression with potential implications on survival. The development of new therapeutic agents targeting the skeletal muscle may thus be beneficial both in ALS and in the age-related sarcopenia context.

Declaration of Conflicts of Interest:

None declared.

Declaration of Sources of Funding:

None declared.

References