Smoking, undernutrition and sarcopenia

At the metabolic level, a key contributor of skeletal muscle catabolism leading to muscle atrophy is a chronic period of negative energy balance^{(Reference Carbone, McClung and Pasiakos12)}. This metabolic state predisposes a catabolic environment with the loss of both fat and lean tissue mass^{(Reference Beaudart, Sanchez-Rodriguez and Locquet26–Reference Sousa-Santos, Afonso and Borges28)}. A negative energy balance has been shown to suppress the activation of insulin-like growth factor 1 (IGF-1) and the mechanistic target of rapamycin complex 1 (mTORC1) cascade, leading to impaired rates of MPS and increased transcription of muscle atrophy-related genes, including myostatin and ubiquitin–proteasome system (UPS) that up-regulate MPB^{(Reference Carbone, McClung and Pasiakos12)}. The stimulation of MPS is an energetically expensive process, and thus, maintenance of muscle mass during an energy deficit is metabolically challenging^{(Reference Carbone, McClung and Pasiakos12)}. Previous studies have revealed associations between smoking and lower body mass index (BMI). Moreover, pre-clinical weight loss studies have demonstrated reductions in BMI to be associated with increased smoking duration^{(Reference Audrain-Mcgovern and Benowitz29–Reference MacKay, Gray and Pell32)}. Hence, a clinical link appears to exist between smoking status, undernutrition and subsequent risk of sarcopenia.

The causal mechanisms that underpin the impact of smoking on appetite, energy balance and muscle protein metabolism are detailed in Fig. 1. The anorexic effects of smoking primarily relate to the nicotine content of cigarettes^{(Reference Jo, Talmage and Role33)}. Previous studies demonstrate that food intake is modulated by β2-, β3-, β4-, α3-, α4-, α5-, α6- and α7-nicotinic acetylcholine receptor (nAChR) subtypes^{(Reference Gotti, Zoli and Clementi34–Reference Sanjakdar, Maldoon and Marks38)}, which act primarily in the arcuate nucleus of the ventral hypothalamus and are responsible for the control of feeding patterns and energy expenditure^{(Reference Sainsbury and Zhang39,Reference Mineur, Abizaid and Rao40)} . A change in energy balance with smoking occurs via neurons and appetite-related hormones in the central and peripheral nervous system that are stimulated by nAChR receptor subtypes. Specifically, nicotine administration stimulates pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript^{(Reference Martínez De Morentin, Whittle and Fernø41,Reference Chen, Hansen and Jones42)} , but down-regulates feeding-promoting neuropeptide Y and Agouti-related protein^{(Reference Fornari, Pedrazzi and Lippi43,Reference Hussain, Al-Daghri and Al-Attas44)} . In addition, decreased food cravings during smoking are associated with lower acetylated ghrelin and enhanced leptin levels as regulatory hormones of energy balance^{(Reference Kroemer, Wuttig, Bidlingmaier, Zimmermann and Smolka45–Reference Wittekind, Kratzsch and Mergl49)}. Ghrelin receptors are expressed in the nucleus accumbens and the ventral tegmental area leading to dopamine release, which exhibits reward properties^{(Reference Han, Frasnelli and Zeighami50,5Reference Verplaetse and McKee1)}. It follows that nAChR receptors decrease the food rewarding properties associated with activation of mesolimbic dopamine neurons, leading to a decreased appetite of sweet and calorically dense foods^{(52–5Reference Stuart, Hons and Ko7)}. Although dopamine receptors are stimulated via nicotine administration, studies have demonstrated a reduced nicotine-induced reward in obese individuals, suggesting a greater potential of appetite-suppressive effects on food palatability in leaner individuals^{(5Reference Dewidar, Kahl and Pa8,5Reference Altajar and Baffy9)}. Given the addictive properties of nicotine and difficulties associated with long-term smoking abstinence, smoking has the potential to facilitate a chronic period of energy deficit^{(Reference al’Absi, Lemieux and Hodges60)}. Therefore, a reduced appetite due to smoking may lead to a negative energy balance, corresponding to a muscle catabolic response and an increased risk of muscle atrophy.

Fig. 1. Proposed mechanisms underpinning the impact of smoking and nicotine administration on appetite and undernutrition. CART, cocaine- and amphetamine-regulated transcript; IGF-1, insulin-like growth factor 1; MPB, muscle protein breakdown; MPS, muscle protein synthesis; mTORC1, mammalian target of rapamycin complex 1; nAChRs, nicotinic acetylcholine receptors; NPY, neuropeptide Y; POMC, pro-opiomelanocortin; UPS, ubiquitin-proteasome system. Solid arrows denote a direct impact; broken arrows denote an indirect impact; indicates increase; indicates decrease.

Smoking also has been associated with a decrease in Bifidobacterium levels and short-chain fatty acids in the gut microbiota, suggesting that smoking may modify microbial composition^{(Reference Tomoda, Kubo and Asahara61)}. Bifidobacterium and short-chain fatty acids are considered beneficial for metabolic health by improving microbiome diversity, insulin sensitivity and the expression of pro-inflammatory cytokines, which are essential for optimal skeletal muscle function^{(Reference Frampton, Murphy and Frost14,Reference Chambers, Byrne and Morrison62–Reference Le Chatelier, Nielsen and Qin65)} . Accordingly, the interactions between nicotine administration and the gut–brain axis are important in regulating appetite, given that smoking may suppress energy intake and contribute to an energy deficit and subsequent skeletal muscle loss. Also noteworthy is the notion that the gut–brain axis is a complex mechanism that is regulated by multiple factors such as genetics, psychological, social and environmental state, nicotine metabolism, and the gut microbiota. This observation indicates a complex and multifaceted relationship between smoking and suppressed food consumption^{(Reference Hu, Yang and Li66,Reference Nakajima, Fukami and Yamanaka67)} . Moving forward, future human studies are warranted to investigate the relationship between smoking and gastrointestinal hormone regulation to quantify the impact of smoking on muscle protein metabolism and the regulation of muscle mass with advancing age.

Smoking, oral health and muscle loss

The deterioration of oral health and consequential dental implications are restrictive for food choice and mastication, leading to reduced dietary intakes from meat, fruits and vegetables. These commonly consumed food sources are major sources of high-quality protein, vitamins, minerals and dietary fibre^{(Reference Brennan, Spencer and Roberts-Thomson68–Reference Stenman, Ahlqwist and Björkelund72)}. Smoking is associated with poor oral health, which may lead to decreased oral function (e.g. swallowing problems, loss of taste) and compromised food intake, both of which may contribute to an increased incidence of sarcopenia and frailty^{(Reference Bakri, Tsakos and Masood73–Reference Murakami, Hirano and Watanabe77)}. Smoking also may contribute to periodontitis, which manifests as a progressive deterioration of the teeth periodontium leading to chewing difficulties^{(Reference Lertpimonchai, Rattanasiri and Arj-Ong Vallibhakara78)}. In vivo human studies indicate the relationship between poor oral health and periodontitis^{(Reference Lertpimonchai, Rattanasiri and Arj-Ong Vallibhakara78,Reference Hirotomi, Yoshihara and Yano79)} may lead to increases in mitochondrially derived ROS^{(Reference Bullon, David and Luis80)} and lipopolysaccharide (LPS) levels caused by Porphyromonas gingivalis bacterial infection^{(Reference Wang and Ohura81,Reference Bullon, Cordero and Quiles82)} and has been associated with a substantive decline in handgrip strength^{(Reference Hamalainen, Rantanen and Keskinen83)}. Accordingly, the cumulative response of periodontitis may be exacerbated with age, enhancing the development of sarcopenia through malnutrition, increased oxidative stress and inflammatory cytokine activation involved in the impaired stimulation of MPS^{(Reference Barreiro, Peinado and Galdiz84–Reference Takahashi, Maeda and Wakabayashi90)}. In summary, oral health complications associated with smoking may indirectly accelerate the incidence of sarcopenia, highlighting the necessity to maintain oral hygiene during chronic periods of smoking^{(Reference Azzolino, Passarelli and De Angelis91)}. Moving forward, a multidisciplinary approach, including dental professionals, dietitians, nutritionists and geriatricians, may provide optimal oral health care management (i.e. prosthodontic rehabilitation) and personalised dietary counselling, combined with follow-up treatments^{(Reference Azzolino, Passarelli and De Angelis91,Reference Zenthofer, Rammelsberg and Cabrera92)} . Longitudinal studies are required to characterise biomarkers of the progression of periodontitis and understand the risk factors associated with this condition^{(Reference Tonetti, Bottenberg and Conrads93)}.

Smoking, chronic obstructive pulmonary disease and muscle wasting

Smoking is considered the primary cause of COPD, which is characterised by restricted airflow and pulmonary complications^{(Reference Roca, Vargas and Cano94)}. The prevalence of COPD is associated with an increased risk of sarcopenia via systemic inflammation, lower BMI, osteoporosis, cachexia and skeletal muscle weakness^{(Reference Andrianopoulos, Wouters and Pinto-Plata95–Reference Van Den Borst, Koster and Yu100)}. Interestingly, COPD may result in limited exercise capacity through enhanced muscle fatigue and may exacerbate lean mass and bone mineral density losses with advancing age^{(Reference Byun, Cho and Chang101–Reference Eliason, Abdel-Halim and Arvidsson103)}. Accordingly, previous studies have reported a decline in quadriceps muscle mass and isokinetic muscle function in COPD patients compared with healthy age-matched controls^{(Reference Clark, Cochrane and Mackay104–Reference Crul, Testelmans and Spruit107)}. This observation is consistent with previous research that observed reductions in type I and IIA muscle fibres, impaired mitochondrial function and skeletal muscle oxidative capacity in COPD patients, leading to age-related decrements of muscle mass and strength^{(Reference Agustí, Sauleda and Miralles108–Reference Krüger, Dischereit and Seimetz111)}. However, it is worth noting that smoking per se may not be the causal factor in muscle fibre atrophy and instead may serve to contribute to muscle disuse and its subsequent consequences^{(Reference Degens and Alway112)}.

Studies also suggest an association between COPD and hypogonadism, which may be attributed to physical inactivity, weight reduction and systemic inflammation^{(Reference Karadag, Ozcan and Karul113,Reference Laghi, Langbein and Antonescu-Turcu114)} . The gradual weight loss that is experienced in COPD patients may lead to an increased catabolic response of respiratory muscles and elevated levels of inflammatory cytokines, which exacerbates changes in body composition^{(Reference Lainscak, von Haehling and Doehner115–Reference Puente-Maestu, Pérez-Parra and Godoy117)}. Although COPD is a potential contributor of sarcopenia, tobacco smoking may independently lead to impaired rates of MPS, increased oxidative stress, myostatin expression and cytokine production in skeletal muscle^{(Reference Madani, Alack and Richter118–Reference Zhang, Liu and Shi120)}. Consistent with this notion, a series of studies demonstrate an up-regulation of the UPS of MPB, as reflected by increased gene expression of skeletal muscle growth inhibitors such as muscle atrophy F-Box (MAFbx/atrogin-1), muscle RING finger-1 (MuRF1) and myostatin through the deactivation of the Akt pathway in smokers versus non-smokers^{(Reference Petersen, Magkos and Atherton119,Reference Doucet, Russell and Léger121,Reference Foletta, White and Larsen122)} . Accordingly, it has been proposed that increased oxidative stress from aldehydes, carbon monoxide, ROS and reactive nitrogen species circulate to the skeletal muscle and activate the p38 and ERK mitogen-activated protein kinase (MAPK), and the nuclear factor κB (NF-κB) signalling pathway^{(Reference Degens, Gayan-Ramirez and Van Hees123–Reference Talhout, Opperhuizen and van Amsterdam125)}. This overexpression of MAPK may up-regulate the muscle-specific E3 ubiquitin ligases and lead to a greater inflammatory response and up-regulation of MPB in smokers, thus accelerating risk of sarcopenia^{(Reference Degens126–Reference Rom, Kaisari and Aizenbud128)}.

Chronic alcohol consumption and skeletal muscle dysfunction

Akin to tobacco smoking, evidence exists that excessive alcohol consumption exacerbates sarcopenia risk via direct and indirect mechanisms related to impaired skeletal muscle protein metabolism^{(Reference Preedy, Adachi and Ueno129–Reference Pruznak, Nystrom and Lang131)}, as depicted in Fig. 2.

Fig. 2. Indirect and direct mechanisms that may underpin the decline in muscle mass and function with smoking and excessive alcohol consumption. 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1; AMPK, AMP-activated protein kinase; IGF-1, insulin-like growth factor 1; IL-1, interleukin 1; IL-6, interleukin 6; IL-10, interleukin 10; MPB, muscle protein breakdown; MPS, muscle protein synthesis; mTOR, mammalian target of rapamycin; REDD1, regulated in development and DNA damage responses 1; S6K1, ribosomal protein S6 kinase 1; TNF-α, tumour necrosis factor-alpha; UPS, ubiquitin proteasome system. Solid arrows denote a direct impact; broken arrows denote an indirect impact; indicates increase; indicates decrease.

The association between excessive alcohol consumption and gut microbiota dysbiosis is supported by studies that reveal hepatic and intestinal inflammation in humans^{(Reference Capurso and Lahner132–Reference Mutlu, Gillevet and Rangwala135)}. In particular, reduced Bacteroidetes and Lactobacillus, and increased Proteobacteria, Fusobacteria and Bacilli species are common in chronic alcoholics versus healthy patients^{(Reference Chen, Yang and Lu133,Reference Mutlu, Gillevet and Rangwala135)} . Conversely, positive outcomes in the microbiome also have been highlighted by moderate red wine consumption, potentially due to its polyphenol content and prebiotic benefits^{(Reference Queipo-Ortuno, Boto-Ordonez and Murri136,Reference Bjørkhaug, Aanes and Neupane137)} . Alcohol-induced microbial dysbiosis has the potential to cause or progress liver diseases and facilitate further disruptions in liver metabolism^{(Reference Frazier, DiBaise and McClain138–Reference Schnabl and Brenner140)}. Hepatic damage that results from altered microbial composition, increased intestinal permeability and circulating endotoxins (e.g. LPS) may progressively lead to subsequent systemic inflammation and insulin resistance, which are common in sarcopenic populations^{(Reference Ghosh, Lertwattanarak and De Jesus Garduño141–Reference Norman, Pirlich and Schulzke145)}. Increased circulating LPS levels may lead to greater pro-inflammatory cytokine secretion, inducing muscle atrophy and mitochondrial dysfunction, which is prevalent in muscle-wasting conditions^{(Reference Marzetti, Lorenzi and Landi146)}. It follows that skeletal muscle dysfunction may be mediated by a combination of cellular senescence, the up-regulation of UPS, unfolding of MPB regulators, and FoXO1/3 signalling pathways^{(Reference Milan, Romanello and Pescatore147)}.

It has been proposed that a variety of catabolic mechanisms are impacted by chronic exposure to ethanol and contribute to skeletal muscle atrophy^{(Reference Buchmann, Spira and König148)}. Increased ethanol intake (>40 g/d; 7–14 drinks per week in women–men, respectively) may cause impaired ureagenesis and hepatocyte injury, stimulating high ammonia concentrations^{(Reference Aagaard, Thøgersen and Grøfte149–Reference Jayasekara and English155)}. This observation may result in hyperammonemia, which dysregulates skeletal muscle proteostasis^{(Reference Hong-Brown, Frost and Lang156–Reference Steiner and Lang158)}. The increase in skeletal muscle ammonia uptake is suggested to up-regulate autophagy and impair MPS, thus increasing sarcopenia risk^{(Reference Fernandez-Solà, Preedy and Lang159,Reference Thapaliya, Runkana and McMullen160)} . Using a rodent model, excess administration of ethanol suppressed protein synthesis rates at the whole-body (−41 %) and skeletal muscle (−75 %) level^{(Reference Tiernan and Ward161)}, and resulted in the up-regulation of muscle-specific E3 ligases, atrogin-1 and MuRF1, leading to muscle proteolysis^{(Reference Vary, Frost and Lang162)}. Furthermore, alcohol consumption following concurrent exercise may impair cellular homeostasis and trigger intramyocellular apoptosis, and subsequently inhibit post-exercise rates of MPS^{(Reference Smiles, Parr and Coffey163)}. Similarly, there is evidence that alcohol consumption inhibits MPS and up-regulates UPS and AMP-activated protein kinase (AMPK) phosphorylation during exercise recovery^{(Reference Barnes, Mündel and Stannard164–Reference Vancampfort, Hallgren and Vandael168)} and following muscle injury and immobilisation^{(Reference Dekeyser, Clary and Otis169,Reference Vargas and Lang170)} . Accordingly, alcohol consumption may inhibit muscle adaptations to resistance training in population groups (i.e. athletes) that aim to enhance muscle mass and function. Importantly, these observations also likely apply to older adult binge drinkers, who are consequently at greater risk of sarcopenia than social drinkers^{(Reference Il, Ha and Lee130,Reference Silveira, De Souza and Silva171)} . Moreover, the inhibitory effect of systemic inflammation on rates of MPS may be additive when excessive alcohol consumption and smoking are combined. Although human trials are lacking to evaluate the direct effect of combined tobacco and ethanol intake on skeletal muscle protein metabolism, oral flora modifications from aldehydes (i.e. acetaldehyde) via both smoking and alcohol exposure may enhance hyperammonemia and autophagy, and the expression of muscle myostatin, MAFbx and down-regulatory mechanisms of MPS^{(Reference Petersen, Magkos and Atherton119,Reference Husain, Scott and Reddy172)} . Future work also is necessary to compare the combined impact of excess alcohol consumption and electronic cigarettes (i.e. vaping) or conventional cigarette smoking on muscle protein metabolism and musculoskeletal health outcomes in older adults.

Multiple studies have investigated the impact of chronic alcohol consumption on skeletal muscle metabolism using rodent models, and have observed reduced basal rates of MPS^{(Reference Korzick, Sharda and Pruznak173–Reference Lang, Pruznak and Deshpande175)}. Both in vivo ^{(Reference Hong-Brown, Frost and Lang156,Reference Hong-Brown, Brown and Navaratnarajah176)} and in vitro ^{(Reference Lang, Pruznak and Deshpande175,Reference Lang, Pruznak and Nystrom177,Reference Lang, Frost and Deshpande178)} studies have demonstrated that alcohol consumption impairs the muscle protein synthetic machinery via decreased activation of mTORC1, ribosomal protein S6 kinase 1 (S6K1) and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). This down-regulation of mTORC-1 signalling with chronic alcohol consumption may be initiated via increased AMPK, REDD1 (regulated in development and DNA damage responses 1) and myostatin activation^{(Reference Steiner and Lang158,Reference Lang, Frost and Svanberg179)} , as well as decreased plasma and muscle insulin-like growth factor I (IGF-I), which is known to activate the mTORC1 signalling pathway^{(Reference Lang, Pruznak and Deshpande175,Reference Nguyen, Le and Tong180)} . In summary, there is accumulating evidence that inhibiting mTORC1-related mechanisms with an increase in habitual alcohol intake attenuates MPS. However, follow-up pre-clinical human trials are warranted to definitively determine the impact of chronic excess alcohol consumption on skeletal muscle protein metabolism and subsequent onset of sarcopenia.