Editing Weakness (section)

==Differential diagnosis==

===True vs. perceived weakness===
* True weakness (or neuromuscular) describes a condition where the force exerted by the muscles is less than would be expected, for example [[muscular dystrophy]].
* Perceived weakness (or non-neuromuscular) describes a condition where a person feels more effort than normal is required to exert a given amount of force but actual muscle strength is normal, for example.<ref>{{cite book | title=Adams and Victor's Principles of Neurology, Ninth Edition | publisher=McGraw-Hill |author1=Ropper, Allan H. |author2=Samuels, Martin A. | author-link=Chapter 24. Fatigue, Asthenia, Anxiety, and Depressive Reactions | year=2009 | isbn=978-0071499927}}</ref>

In some conditions, such as [[myasthenia gravis]], muscle strength is normal when resting, but ''true weakness'' occurs after the muscle has been subjected to exercise. This is also true for some cases of [[Myalgic encephalomyelitis/chronic fatigue syndrome]], where objective post-exertion muscle weakness with delayed recovery time has been measured and is a feature of some of the published definitions.<ref>{{cite journal |doi=10.1046/j.1468-1331.1999.610063.x |vauthors=Paul L, Wood L, Behan WM, Maclaren WM |title=Demonstration of delayed recovery from fatiguing exercise in chronic fatigue syndrome |journal=Eur. J. Neurol. |volume=6 |issue=1 |pages=63–9 |date=January 1999 |pmid=10209352 |s2cid=33480143 }}</ref><ref>{{cite journal |doi=10.1042/CS19980372 |vauthors=McCully KK, Natelson BH |title=Impaired oxygen delivery to muscle in chronic fatigue syndrome |journal=Clin. Sci. |volume=97 |issue=5 |pages=603–8; discussion 611–3 |date=November 1999 |pmid=10545311 }}</ref><ref>{{cite journal |doi=10.1001/archinte.160.21.3270 |vauthors=De Becker P, Roeykens J, Reynders M, McGregor N, De Meirleir K |title=Exercise capacity in chronic fatigue syndrome |journal=Arch. Intern. Med. |volume=160 |issue=21 |pages=3270–7 |date=November 2000 |pmid=11088089 |url=http://archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=11088089 |doi-access= |access-date=2011-03-12 |archive-date=2011-08-12 |archive-url=https://web.archive.org/web/20110812232955/http://archinte.ama-assn.org/cgi/content/full/160/21/3270 |url-status=dead |url-access=subscription }}</ref><ref>{{cite journal |doi=10.1046/j.1365-2796.2001.00890.x |vauthors=De Becker P, McGregor N, De Meirleir K |title=A definition-based analysis of symptoms in a large cohort of patients with chronic fatigue syndrome |journal=J. Intern. Med. |volume=250 |issue=3 |pages=234–40 |date=September 2001 |pmid=11555128  |doi-access=free }}</ref><ref>{{cite book |first1=Bruce M. |last1=Carruthers |first2=Anil Kumar |last2=Jain |first3=Kenny L. |last3=De Meirleir |first4=Daniel L. |last4=Peterson |first5=Nancy G. |last5=Klimas |first6=A. Martin |last6=Lerner |first7=Alison C. |last7= Bested |first8=Pierre |last8=Flor-Henry |first9=Pradip |last9=Joshi |first10=A. C. Peter |last10=Powles |first11=Jeffrey A. |last11=Sherkey |first12=Marjorie I. |last12=van de Sande |display-authors=5 |title=Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols |journal=Journal of Chronic Fatigue Syndrome |volume=11 |issue=1 |pages=7–115 |year=2003 |isbn=978-0-7890-2207-3 |issn=1057-3321 |doi=10.1300/J092v11n01_02}}</ref><ref>{{cite journal |vauthors=Jammes Y, Steinberg JG, Mambrini O, Brégeon F, Delliaux S |title=Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise |journal=J. Intern. Med. |volume=257 |issue=3 |pages=299–310 |date=March 2005 |pmid=15715687 |doi=10.1111/j.1365-2796.2005.01452.x |doi-access=free }}</ref>

==={{anchor|Asthenia}}Asthenia vs. myasthenia===
'''Asthenia''' or '''asthaenia''' ({{langx|el|ἀσθένεια}}, literally ''lack of strength'' but also ''disease'') is a medical term referring to a condition in which the body lacks or has lost strength either as a whole or in any of its parts. It is a poorly defined condition that can include true or primary [[muscle weakness]] or perceived muscle weakness.<ref>{{Citation |last1=Kauffman |first1=Timothy L. |title=Chapter 16 - Muscle weakness and therapeutic exercise |date=2014-01-01 |url=https://www.sciencedirect.com/science/article/pii/B9780702045882000164 |work=A Comprehensive Guide to Geriatric Rehabilitation (Third Edition) |pages=112–119 |editor-last=Kauffman |editor-first=Timothy L. |access-date=2023-11-19 |place=Oxford |publisher=Churchill Livingstone |isbn=978-0-7020-4588-2 |last2=Kemmis |first2=Karen |editor2-last=Scott |editor2-first=Ron |editor3-last=Barr |editor3-first=John O. |editor4-last=Moran |editor4-first=Michael L.}}</ref> For perceived muscle weakness, asthenia has been described as the feeling of weak or tired muscles in the absence of muscle weakness, that is the muscle can generate a normal amount of force but it is perceived as requiring more effort.<ref name=":0">{{Cite journal |last=Saguil |first=Aaron |date=2005-04-01 |title=Evaluation of the Patient with Muscle Weakness |url=https://www.aafp.org/pubs/afp/issues/2005/0401/p1327.html |journal=American Family Physician |language=en-US |volume=71 |issue=7 |pages=1327–1336 |pmid=15832536 |quote=Asthenia is a sense of weariness or exhaustion in the absence of muscle weakness.}}</ref><ref>{{Cite web |date=2021-06-28 |title=Muscle Weakness and Fatigue {{!}} Causes and Treatment |url=https://patient.info/signs-symptoms/tiredness-fatigue/muscle-weakness |access-date=2023-11-19 |website=patient.info |language=en |quote=Muscle tiredness: This is sometimes called asthenia. It is a sense of weariness or exhaustion that you feel when using the muscle. The muscle isn't genuinely weaker, it can still do its job but it takes you more effort to manage it.}}</ref>

General asthenia occurs in many chronic wasting diseases (such as tuberculosis and cancer), sleep disorders or chronic disorders of the heart, lungs or kidneys, and is probably most marked in diseases of the adrenal gland. Moreover, asthenia can be a symptom of [[mast cell activation syndrome|mast cell activation syndrome (MCAS)]].<ref name="PMID27012973">{{cite journal |vauthors=Afrin LB, Butterfield JH, Raithel M, Molderings GJ |title=Often seen, rarely recognized: mast cell activation disease--a guide to diagnosis and therapeutic options |journal=The American Journal of the Medical Science |volume=48 |issue=3 |date=2016 |pages=190-201 |DOI=10.3109/07853890.2016.1161231 |PMID=27012973 |url=|doi-access=free}}</ref> Asthenia may be limited to certain [[organ (anatomy)|organs]] or systems of organs, as in [[asthenopia]], characterized by ready fatiguability. Asthenia is also a side effect of some medications and treatments, such as [[Ritonavir]] (a [[Protease inhibitor (pharmacology)|protease inhibitor]] used in [[HIV]] treatment). <ref>{{Cite web |date=28 November 2022 |title=PubChem Compound Summary for CID 392622, Ritonavir |url=https://pubchem.ncbi.nlm.nih.gov/compound/ritonavir |access-date=28 November 2022 |website=NCBI}}</ref> 

Differentiating psychogenic (perceived) asthenia and true asthenia from myasthenia is often difficult, and in time apparent psychogenic asthenia accompanying many chronic disorders is seen to progress into a primary weakness.{{citation needed|date=August 2021}}

Myasthenia or myasthaenia (my- from {{langx|el|μυο}} meaning "muscle" + -asthenia [''{{lang|el|ἀσθένεια}}''] meaning "weakness"), or simply muscle weakness, is a lack of muscle strength. The causes are many and can be divided into conditions that have either true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, including muscular dystrophy and inflammatory myopathy. It occurs in [[neuromuscular disease]]s, such as myasthenia gravis. Perceived muscle weakness occurs in diseases such as sleep disorders, and depression.<ref name=":0" />

===Types===
Muscle fatigue can be central, neuromuscular, or peripheral muscular. Central muscle fatigue manifests as an overall sense of energy deprivation, and peripheral muscle weakness manifests as a local, muscle-specific inability to do work.<ref>{{cite book |vauthors=Gandevia SC, Enoka RM, McComas AJ, Stuart DG, Thomas CK |title=Fatigue |chapter=Neurobiology of Muscle Fatigue |volume=384 |pages=515–25 |year=1995 |pmid=8585476 | doi = 10.1007/978-1-4899-1016-5_39|series=Advances in Experimental Medicine and Biology |isbn=978-1-4899-1018-9 }}</ref><ref>{{cite journal |author=Kent-Braun JA |title=Central and peripheral contributions to muscle fatigue in humans during sustained maximal effort |journal=European Journal of Applied Physiology and Occupational Physiology |volume=80 |issue=1 |pages=57–63 |year=1999 |pmid=10367724 |doi=10.1007/s004210050558|s2cid=22515865 }}</ref> Neuromuscular fatigue can be either central or peripheral.{{citation needed|date=August 2021}}

====Central fatigue====
The central fatigue is generally described in terms of a reduction in the [[nervous system|neural]] drive or nerve-based motor command to working muscles that results in a decline in the force output.<ref>{{cite journal |author=Gandevia SC |title=Spinal and supraspinal factors in human muscle fatigue |journal=Physiol. Rev. |volume=81 |issue=4 |pages=1725–89 |year=2001 |pmid=11581501 |doi=10.1152/physrev.2001.81.4.1725 }}</ref><ref>{{cite journal |vauthors=Kay D, Marino FE, Cannon J, St Clair Gibson A, Lambert MI, Noakes TD |title=Evidence for neuromuscular fatigue during high-intensity cycling in warm, humid conditions |journal=Eur. J. Appl. Physiol. |volume=84 |issue=1–2 |pages=115–21 |year=2001 |pmid=11394239 |doi=10.1007/s004210000340|s2cid=25906759 }}</ref><ref>{{cite journal |doi=10.3109/13813459109145909 |vauthors=Vandewalle H, Maton B, Le Bozec S, Guerenbourg G |title=An electromyographic study of an all-out exercise on a cycle ergometer |journal=Archives Internationales de Physiologie, de Biochimie et de Biophysique |volume=99 |issue=1 |pages=89–93 |year=1991 |pmid=1713492 }}</ref>  It has been suggested that the reduced neural drive during exercise may be a protective mechanism to prevent organ failure if the work was continued at the same intensity.<ref>{{cite journal |vauthors=Bigland-Ritchie B, Woods JJ |title=Changes in muscle contractile properties and neural control during human muscular fatigue |journal=Muscle Nerve |volume=7 |issue=9 |pages=691–9 |year=1984 |pmid=6100456 |doi=10.1002/mus.880070902|s2cid=13606531 }}</ref><ref>{{cite journal |author=Noakes TD |title=Physiological models to understand exercise fatigue and the adaptations that predict or enhance athletic performance |journal=Scandinavian Journal of Medicine & Science in Sports |volume=10 |issue=3 |pages=123–45 |year=2000 |pmid=10843507 |doi=10.1034/j.1600-0838.2000.010003123.x|s2cid=23103331 }}</ref> The exact mechanisms of central fatigue are unknown, though there has been considerable interest in the role of [[serotonin|serotonergic]] pathways.<ref>{{cite journal |author=Davis JM |title=Carbohydrates, branched-chain amino acids, and endurance: the central fatigue hypothesis |journal=International Journal of Sport Nutrition |volume=5 |issue=Suppl |pages=S29–38 |year=1995 |pmid=7550256 |doi=10.1123/ijsn.5.s1.s29 }}</ref><ref>Newsholme, E. A., Acworth, I. N., & Blomstrand, E. 1987, 'Amino acids, brain neurotransmitters and a functional link between muscle and brain that is important in sustained exercise', in  G Benzi (ed.), Advances in Myochemistry, Libbey Eurotext, London, pp. 127-133.</ref><ref>{{cite book |vauthors=Newsholme EA, Blomstrand E |chapter=Tryptophan, 5-Hydroxytryptamine and a Possible Explanation for Central Fatigue |title=Fatigue |volume=384 |pages=315–20 |year=1995 |pmid=8585461 |doi=10.1007/978-1-4899-1016-5_25|series=Advances in Experimental Medicine and Biology |isbn=978-1-4899-1018-9 }}</ref>

====Neuromuscular fatigue====
[[Nerve]]s control the contraction of muscles by determining the number, sequence, and force of muscular contraction. When a nerve experiences [[synaptic fatigue]] it becomes unable to stimulate the muscle that it innervates. Most movements require a force far below what a muscle could potentially generate, and barring [[pathology]], neuromuscular fatigue is seldom an issue.{{citation needed|date=August 2021}}

For extremely powerful contractions that are close to the upper limit of a muscle's ability to generate force, neuromuscular fatigue can become a limiting factor in untrained individuals. In novice [[strength training|strength trainers]], the muscle's ability to generate force is most strongly limited by nerve's ability to sustain a [[rate coding|high-frequency signal]]. After an extended period of maximum contraction, the nerve's signal reduces in frequency and the force generated by the contraction diminishes. There is no sensation of pain or discomfort, the muscle appears to simply 'stop listening' and gradually cease to move, often [[Muscle contraction#Eccentric contraction|lengthening]]. As there is insufficient stress on the muscles and tendons, there will often be no [[delayed onset muscle soreness]] following the workout.  Part of the process of strength training is increasing the nerve's ability to generate sustained, high frequency signals which allow a muscle to contract with their greatest force.  It is this "neural training" that causes several weeks worth of rapid gains in strength, which level off once the nerve is generating maximum contractions and the muscle reaches its physiological limit. Past this point, training effects increase muscular strength through myofibrillar or sarcoplasmic [[Muscle hypertrophy#Strength training|hypertrophy]] and metabolic fatigue becomes the factor limiting contractile force.

====Peripheral muscle fatigue====
Peripheral muscle fatigue during physical work is considered{{By whom|date=April 2012}} an inability for the body to supply sufficient energy or other metabolites to the contracting muscles to meet the increased energy demand. This is the most common case of physical fatigue—affecting a national{{Where|date=April 2012}} average of 72% of adults in the work force in 2002. This causes contractile dysfunction that manifests in the eventual reduction or lack of ability of a single muscle or local group of muscles to do work. The insufficiency of energy, i.e. sub-optimal [[cellular respiration|aerobic metabolism]], generally results in the accumulation of [[lactic acid]] and other [[acid]]ic anaerobic metabolic by-products in the muscle, causing the stereotypical burning sensation of local muscle fatigue, though recent studies have indicated otherwise, actually finding that lactic acid is a source of energy.<ref name=robergs>{{cite journal |author1=R. Robergs |author2=F. Ghiasvand |author3=D. Parker | title = Biochemistry of exercise-induced metabolic acidosis | journal = Am J Physiol Regul Integr Comp Physiol | volume = 287 | issue = 3 | pages = R502–16 | year = 2004 | doi = 10.1152/ajpregu.00114.2004 | pmid = 15308499|s2cid=2745168 }}</ref>

The fundamental difference between the peripheral and central theories of muscle fatigue is that the peripheral model of muscle fatigue assumes failure at one or more sites in the chain that initiates muscle contraction. Peripheral regulation  therefore depends on the localized metabolic chemical conditions of the local muscle affected, whereas the central model of muscle fatigue is an integrated mechanism that works to preserve the integrity of the system by initiating muscle fatigue through muscle derecruitment, based on collective feedback from the periphery, before cellular or organ failure occurs. Therefore, the feedback that is read by this central regulator could include chemical and mechanical as well as cognitive cues. The significance of each of these factors will depend on the nature of the fatigue-inducing work that is being performed.{{citation needed|date=August 2021}}

Though not universally used, "metabolic fatigue" is a common alternative term for peripheral muscle weakness, because of the reduction in contractile force due to the direct or indirect effects of the reduction of substrates or accumulation of metabolites within the [[muscle fiber|myocytes]]. This can occur through a simple lack of energy to fuel contraction, or through interference with the ability of Ca<sup>2+</sup> to stimulate [[actin]] and [[myosin]] to contract.